Hedgehog pathway and cancer: A new area (Review)

Shen,Deyi; Xia,Yuwei; Fu,Yuhan; Cao,Qiaochang; Chen,Wenqian; Zhu,Ying; Guo,Kaibo; Sun,Leitao

doi:10.3892/or.2024.8775

Hedgehog pathway and cancer: A new area (Review)

Authors:
- Deyi Shen
- Yuwei Xia
- Yuhan Fu
- Qiaochang Cao
- Wenqian Chen
- Ying Zhu
- Kaibo Guo
- Leitao Sun
View Affiliations

Affiliations: The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, P.R. China, The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China, Department of Cancer Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
Published online on: July 10, 2024 https://doi.org/10.3892/or.2024.8775
Article Number: 116
Copyright: © Shen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

In years of research on classical pathways, the composition, information transmission mechanism, crosstalk with other pathways, and physiological and pathological effects of hedgehog (HH) pathway have been gradually clarified. HH also plays a critical role in tumor formation and development. According to the update of interpretation of tumor phenotypes, the latest relevant studies have been sorted out, to explore the specific mechanism of HH pathway in regulating different tumor phenotypes through gene mutation and signal regulation. The drugs and natural ingredients involved in regulating HH pathway were also reviewed; five approved drugs and drugs under research exert efficacy by blocking HH pathway, and at least 22 natural components have potential to treat tumors by HH pathway. Nevertheless, there is a deficiency of existing studies. The present review confirmed the great potential of HH pathway in future cancer treatment with factual basis.

Introduction

The hedgehog (HH) signaling pathway was first discovered by Nusslein-Volhard and Wieschaus in the 1980s when screening for genes that affect Drosophila embryonic development. In the following decades, the HH pathway was confirmed to be a highly conserved signaling mechanism, widely related to human physiology and pathology (1). Through highly regulated activation, HH coordinates the development of multiple central systems and limb formation in embryos. In adults, HH is mainly involved in stem cell renewal, wound healing, organ homeostasis, tissue repair and tumorigenesis (2,3).

The role of HH is mainly dependent on the signal transduction of the following molecules: Ligand family member protein, HH ligands; two receptors, patched (PTCH) and smoothened (SMO); the nuclear factors, kinesin family member 7, casein kinase 1, suppressor of fused protein (SUFU) and glioma-associated oncogene (GLI); and related target genes (4).

As with several classical signaling pathways, the classical HH pathway is initiated by the binding of ligands to receptors. HH ligands is currently known to have three subtypes in mammals, including sonic HH (SHH), Indian HH (IHH) and desert HH (DHH), of which SHH is the most widely expressed and most active. When ligand is not present (off-state), the coupling receptor, SMO, on intracellular vesicles is inhibited by PTCH, which is located on primary cilia. In the absence of accumulation, SMO cannot transmit HH signal to downstream SUFU and therefore GLI activator (GLI-A) is not released. Instead, a GLI transcriptional repressor is formed to inhibit the expression of the target genes (5). When ligand is available (on-state), ligand binds to and internalizes PTCH, relieving the inhibition of SMO. As a result, full-length GLI receives the relevant signals to form GLI-A and promotes the transcription of HH target genes (4,5). Activation of the classical HH pathway can also be divided into autocrine, paracrine and reverse secretory modes, according to the source of HH ligand. The interaction between tumor cells and tumor stromal cells is realized by such pathways (Fig. 1).

Figure 1.

Classical HH pathway. Activation of the classical HH pathway is dependent on HH ligands, which can be bind to and then internalize PTCH, relieving the inhibition of SMO on the intracellular vesicles, and transmit HH signal to SUFU. Thus, GliFL receives relevant signals to form Gli-A and promotes the transcription process of HH target genes. HH, Hedgehog; PTCH, Patched; SMO, Smoothened; SUFU, suppressor of fused protein; Gli-A, GLI, family zinc finger 1; IHH, Indian HH; DHH, dessert HH; PKA, protein kinase CAMP-activated catalytic subunit alpha; CK1, casein kinase 1 alpha 1; GSK-3β, glycogen synthase kinase 3 beta; b-TrCP, beta-transducin repeat containing E3 ubiquitin protein ligase; Kif7, kinesin family member 7; FOXA2, forkhead box A2; HIP, collagen type II alpha 1 chain.

The specific mechanism of action of the non-classical HH pathway has not yet been fully understood. However, it appears that when the classical pathway cannot function in a cytotoxic or stressful state, the non-classical pathway is an alternative activation pathway for transmitting HH signals (6). In the PTCH-SMO-GLI axis, the key proteins of HH signal transmission can alter their original conformation by coupling with other molecules due to their unique structure, thus regulating target genes without being constrained by upstream/downstream signals, such as apoptosis factors gathering in the C-terminal tail of PTCH or formation of the SMO-Gi (one family of G proteins) protein complex (7). GLI-related non-classical pathways are becoming increasingly prominent in cancer development due to their involvement in a number of signaling pathways known to be related to cancer (8).

Following the research progress on tumorigenesis and development, oncologists have summarized the characteristic parameters of tumors into 14 types (9), which has provided a logical framework for understanding the notable diversity of tumors. There is sufficient evidence to support that abnormal expression of the HH pathway manipulates tumor cell growth, proliferation, survival, angiogenesis and metastasis and the metabolic reprogramming of tumor cells and the microenvironment (10,11).

Based on the relationship between the HH pathway and cancer phenotype, the present review mainly discusses the molecular mechanisms identified in the latest discoveries of the HH pathway in tumorigenesis and development, as well as the related factors regulating these phenotypic changes. Several molecular synthetic and natural drugs that have been revealed to inhibit abnormal activation of HH are also summarized, for exploring the possibility of treating related cancer types (Fig. 2).

Figure 2.

Influences of HH pathway on cancer phenotype. Information interaction between tumor cells and tumor stromal cells can be realized via HH pathway. This eventually regulates genome instability mutation, non-mutational epigenetic reprogramming, tumor promoting inflammation, immune destruction, senescent cells, invasion and metastasis, accessing vasculature, and cellular metabolism. HH, Hedgehog; PTCH, patched; SMO, smoothened; SUFU, suppressor of fused protein.

Genome instability mutations

Single-gene mutation

According to the current understanding, cancer tends to be defined as a group of malignant diseases with multiple genetic origins. Therefore, gene mutations cannot be ignored in the occurrence of cancer. In normal tissues and organs, the HH pathway is a crucial pathway for development. For instance, the HH pathway controls the migration of granular neuronal precursors to the correct location in the brain (12). Once mutation of HH occurs, the opportunity for tumorigenesis occurs. According to the 2021 World Health Organization guidelines, medulloblastomas can be divided into four molecular subgroups, of which the evaluation is partially based on HH genotyping (13).

Gorlin syndrome (GS), a rare autosomal dominant disease, is caused by mutations in the HH pathway. The typical mutations observed in GS cause pathogenic variations of PTCH1 and SUFU. In the differential diagnosis of GS, it has been suggested that PTCH2 may be a candidate gene for the prediction of susceptibility, and mutation of PTCH2 has been reported in clinical practice (14). However, a recent study asserted that PTCH2 should not be included in the genetic diagnosis of GS (15). In fact, the PTCH2 gene has different functional characteristics to PTCH1. PTCH2 is considered to coordinate PTCH1 to alter SMO localization and plays an auxiliary role in regulating the HH pathway (12). This may explain the absence of a statistically significant detection of PTCH2 mutations in the clinic.

A recent study indicated that 68% of SUFU pathogenic variation carriers had at least one type of tumor, and the incidence of tumors in their relatives reached 44.1% in individuals up to 50 years-old (16).

SMO mutations have also attracted wide attention due to resistance mutations that prevent effective drug binding (discussed later). In addition, carcinogenic mutation of SMO is widespread. In this instance, the mutation stabilizes the active form of SMO and releases it from the conformational restriction of the inactive state, and thus may induce clonal expansion together with tumor initiation and invasion (17). SMO multi-site mutations have been revealed to be a carcinogenic driver for a variety of epithelial-derived tumors and brain tumors (18).

GLI mutations have also been reported in the clinic. In addition, a study has suggested that upregulation of a GLI2-β subtype lacking the N-terminal repressor domain induced chromosome number and structure aberrations, which disrupt genomic stability (19).

Mutation and tumor type

The latest version of COSMIC v99 (released November, 28 2023; http://cancer.sanger.ac.uk) was used to summarize the mutation rate of key molecules in the HH pathway in different tumor types. As demonstrated in Tables I, SI and SII, except for central nervous system medulloblastoma (SHH subtype) and basal cell carcinoma, alimentary tract cancer and adenocarcinoma demonstrated a higher incidence of HH pathway mutation. However, the latter two tumors have not markedly benefited from HH pathway inhibitors. It is considered that some pathway inhibitors affect gene expression due to their diverse treatment mechanism and rich therapy targets, as well as crosstalk with other pathways and epigenetic reprogramming.

Table I.

Single gene mutation rates of key genes in Hedgehog pathway in different tumor types.

Multi-gene fusion

In addition to single-gene mutations, multi-gene fusion has also received attention in research. Common gene fusions occur between GLI1 and other genes (Table SII). At present, the MALAT1-GLI1 gene fusion has been identified as one of the diagnostic criteria for gastroblastoma (20). Regardless of the concrete types of multi-gene fusion, inhibition of HH can be used as a general treatment method. Furthermore, the upregulation of GLI1 has been defined as an alternative genetic mechanism for GLI1 fusions, with the characteristics of co-amplification of the cyclin-dependent kinase (CDK) 4 and MDM2 genes (21,22).

Non-mutational epigenetic reprogramming

HH and methylation

In addition to altering the DNA sequence, DNA can also be chemically modified by methylation and hydroxy-methylation to regulate gene expression (23,24). By querying the MethMarkerDB database (https://methmarkerdb.hzau.edu.cn/) (25), the overall degree of methylation of HH pathway-related genes was determined and the potential of differentially methylated regions for the diagnosis (Table SIII) and prognosis (Table SIV) of some cancer types was underscored. Among them, the low methylation level and high expression of GLI1 in melanoma, GLI2 in ocular melanomas and GLI3 in stomach cancer suggested an improved patient prognosis. PTCH1 in kidney clear cell carcinoma and GLI3 in colon and prostate cancer were also considered to be robust diagnostic biomarkers. In addition, clinical data supports the suggestion that promoter methylation is a critical regulatory mechanism of SHH (26), PTCH, GLI (27) and SMO (28) expression. Accordingly, folic acid (29) and DNA methyltransferase inhibitors (27) can effectively block the HH pathway for the treatment of cancer.

HH and histone modification

Notable heterogeneity in methylation and gene expression levels were also observed in the MethMarkerDB data (Tables SIII and SIV). This heterogeneity may be ascribed to the limited sample size. However, abnormal epigenetic characteristics of cancer cells can also be induced by phosphorylation, acetylation and other acylation modifications of histones in cellular chromatin (23,24). The phosphorylation of GLI1 can be disrupted by mutations in AMP-activated protein kinase (AMPK), which increases carcinogenic potency. As acetylated proteins, GLI1 and GLI2 rely on histone deacetylase (HDAC)-mediated deacetylation to promote transcriptional activation. HDAC-related changes also directly lead to changes in GLI. Therefore, HH and HDAC inhibitors may exert a synergistic antitumor effect (30). Additional modifications include: Sufu negating protein 1 ubiquitinates SUFU via ligand of numb-protein X 1 (31), runt-related transcription factor 3 promotes GLI ubiquitination (10) through the E3 ubiquitin ligase family (32) and protein phosphatase 4 regulatory subunit 2 promotes SUFU dephosphorylation (33).

HH and non-coding (nc) RNA

Recent developments in the research of ncRNA have attracted marked attention, particularly microRNA (miRNA), which plays a regulatory role by directly cutting or preventing the translation of mRNA. In addition, circular RNA, rich with miRNA binding sites, can sponge miRNA to relieve the inhibition of mRNA. The binding of long ncRNAs to RNA-binding proteins confers a variety of regulatory functions, including managing genomic instability. The specific regulation of key molecules of the HH pathway by ncRNAs is summarized in Table II (11,34–127). As summarized in Table SV, the HH pathway can also affect the expression of other pathway molecules by regulating ncRNA to regulate tumor phenotypes.

Table II.

The specific regulation of key molecules of the HH pathway by ncRNAs.

Table II.

The specific regulation of key molecules of the HH pathway by ncRNAs.

Non-coding RNA		Effects	Tumor type	Phenotype	(Refs.)
Long non-	BBOX1-AS1	Sponge miR-506-5p to up-regulate	Esophageal squamous cell	Promote tumor proliferation and	(34)
coding RNAs		EIF5A, stabilize PTCH1 mRNA	carcinoma	stemness
	HHIP-AS1	Block miR-425-5p-dependent	Medulloblastoma Atypical	Promote mitosis	(35)
		inhibition of DYNC1I2 expression	teratoid/rhabdoid tumor
		Stabilize HHIP mRNA	Lung squamous cell carcinoma	Inhibiting cell proliferation and	(36)
				migration
		Target CELF2/stabilize HHIP	Non-small-cell lung cancer	Reduce tumor proliferation,	(37)
		mRNA		migration, and invasion
	HIF1A-AS2	Bind to GLI1, upregulate HIF1a	Clear cell renal cell carcinoma	Promote tumor proliferation and	(38)
		expression		migration
	LIFR-AS1	Sponge miR-197-3p/reduce SUFU	Breast cancer	Promote tumor proliferation,	(39)
		expression		migration and invasion
	LINC00475	Sponge miR-340-5p/increase SHH	Hepatocellular carcinoma	Promote tumor proliferation,	(40)
		expression		migration, and invasion
				Reduce apoptosis
	LINC00641	Competitively bind to IGF2BP1/	Papillary thyroid carcinoma	Reduce tumor proliferation and	(41)
		destabilize GLI1 mRNA		invasion, Reduce apoptosis
	LINC01093	Competitively bind to IGF2BP1/	Hepatocellular carcinoma	Reduce tumor proliferation and	(42)
		destabilize GLI1 mRNA		metastasis
	LINC01106	Increase GLI1, GLI2 and GLI4	Colorectal cancer	Promote tumor proliferation,	(43)
		expression		migration, and stemness
	LINC01426	Promote SHH deubiquitination	Lung adenocarcinoma	Promote EMT, tumor proliferation,	(44)
				migration, and stemness
	LINC01503	Transcript ENST00000444125	Glioblastoma	Promote tumor stemness	(45)
		reduce GLI2 ubiquitination,
		partially attenuated FBXW1
		overexpression induced GLI2
		ubiquitination
	LINC01510	Sponge miR-34b-5p/decrease	Papillary thyroid carcinoma	Reduce tumor proliferation,	(46)
		GLI1 expression		migration and invasion
	LOC101930370	Sponging miR-1471/ induce SHH	Breast cancer	Promote tumor growth and	(47)
		expression		tumorigenesis
	lncRNA-	Increase SMO and GLI1	Cholangiocarcinoma	Promote tumor proliferation,	(48)
	ASAP1-IT1	expression		migration, and EMT
	lncRNA-ANCR	Bind to PTCH, upregulate	Basal cell carcinoma	Promote tumor proliferation,	(49)
		N-cadherin, vimentin, β-catenin,		invasion, and migration
		PTCH, GLI1, and SMO expre-		Reduce apoptosis
		ssion, and downregulate E-
		cadherin expression
	lncRNA-	Increase GLI2 expression	Osteosarcoma	Promote tumor growth and	(50)
	BCAR4			migration
		Increase GLI2 expression	Non-small cell lung cancer	Promote tumor migration, invasion	(51)
	lncRNA-
	BLACAT1	Increase SHH, GLI1 and SMO	Non-small cell lung cancer	Promote tumor proliferation,	(52)
		expression		migration, and invasion
	lncRNA-cCSC1	Increase SMO and GLI1	Colorectal cancer	Promote tumor proliferation,	(53)
		expression		migration, invasion, stemness
	lncRNA-	Sponge miR-328/reduce GLI1,	Hepatocellular carcinoma	Reduce tumor proliferation,	(54)
	DIO3OS	GLI2, and GLI3 expression		migration, and invasion
	lncRNA-EGOT	Increase GLI1 expression	Breast cancer	Promote tumor proliferation, and	(55)
				migration
		Increase SHH, SUFU and GLI1	Gastric cancer	Promote tumor proliferation and	(56)
		expression		metastasis
	lncRNA-GAS5	Downregulate miR-378a-5p/induce	Triple-negative breast cancer	Promote tumor apoptosis	(57)
		SUFU expression
	lncRNA-	Sponge miR-140/increase SHH,	Nasopharyngeal carcinoma	Promote tumor proliferation,	(58)
	HCG18	GLI1 expression		metastasis, Reduce apoptosis
	lncRNA-	Reduce PTCH1 expression	Hepatocellular carcinoma	Promote CSCs self-renewal ability	(59)
	HDAC2
	lncRNA-	Interact with androgen receptor,	Renal cell carcinoma	Promote tumor angiogenesis and	(60)
	HOTAIR	and cooperatively bind to GLI2		stemness
		promoter and increase GLI2
		expression
		Increase GLI1 expression	Non-small cell lung cancer	Promote proliferation, migration,	(61)
				and invasion. Promote acquired
				resistance to EGFR-TKIs
	lncRNA-Hh	Targets GAS1 to activate Hh	Breast cancer	Promote CSCs enrichment, self-	(62)
		signaling pathway		renewal, and mammosphere-
				formation efficiency
	lncRNA-	Sponge hsa-miR-202/induce GLI2	Gastric cancer	Promote tumor proliferation	(63)
	MALAT1	expression		Reduce apoptosis
		Encoding region show transcrip-	Plexiform fibromyxoma	Promote expression of truncated	(64)
		tional regulatory activity for the	Gastroblastoma	GLI1
		MALAT1:GLI1 fusion gene
	lncRNA-	Increase GLI2 expression via	Non-small-cell lung cancer	Promote drug resistance, tumor	(65)
	MIR31HG	WDR5/MLL3/P300 complex-		invasion, and stemness
		mediated H3K4me and H3K27Ace
		modification
	lncRNA	Sponge miR-34b-5p/increase	Diffuse large B-cell lymphoma	Promote tumor proliferation	(66)
	NEAT1	GLI1 expression		Reduce apoptosis
	lncRNA-	Form a positive loop with the	Non-small-cell lung cancer	Promote stem-like cell proliferation	(67)
	SOX2OT	GLI1, sponge miR-186-5p/increase
		METTL3/14 and IGF2BP2
		expression
		Increase GLI1 expression	Lung adenocarcinoma	Promote tumor proliferation	(68)
	lncRNA-TUG1	Compete with hsa-miR-132/induce	Hepatocellular carcinoma	Promote tumor proliferation	(69)
		SHH expression		Reduce apoptosis
	lncRNA-	Sponge miRNA-802/increase	Esophageal carcinoma	Promote tumor proliferation,	(70)
	SNHG16	PTCH1 expression		colony formation, and self-renewal
Circular	circRNA-	Sequester miR-616-3p/induce	Breast cancer	Promote tumor proliferation and	(71)
RNAs	DCAF6	GLI1 expression		stemness
	circRNA-	Decrease miR-873 expression /	Neuroblastoma	Promote tumor proliferation,	(72)
	DGKB	increase GLI2 expression		migration, invasion
				Reduce apoptosis
	circRNA-	Interact with the heterogeneous	Esophageal squamous cell	Promote tumor proliferation,	(73)
	FIRRE	nuclear ribonucleoprotein C	carcinoma	migration, and invasion
		(HNRNPC) protein to stabilize
		GLI2 mRNA, increase GLI2
		expression
	circRNA-	Sponge miR-29a/b/c-3p/increase	Hepatoblastoma	Promote tumor proliferation,	(74)
	STAT3	STAT3 and Gli2 expression		migration, invasion, and stemness
	circRNA-SMO	Sponge miR-326/increase CEP85	Glioblastoma	promote tumor proliferation and	(75)
		expression		migration
	circRNA-SMO-	Enhance SMO cholesterol	Glioblastoma	Promote tumor stemness, self-	(76)
	193a.a.	modification/SHH/GLI1/FUS/		renewal, proliferation and
		SMO-193a.a. form a positive		tumorigenicity
		feedback loop
	circRNA-	Sponge miR-338-3p/increase SMO	Glioma	Promote tumor proliferation,	(77)
	SMO742	expression		migration, and invasion
				Reduce apoptosis
	circRNA-	Bind to microRNA-150/induce	Colorectal cancer	Promote tumor migration and EMT	(78)
	ZNF609	GLI1 expression
		Decrease miR-15a-5p, miR-15b-	Hepatocellular carcinoma	Promote tumor proliferation,	(79)
		5p expression /increase GLI2		metastasis, and stemness
		expression		Reduce apoptosis
	circRNA-	Sponge miR-541-3p/increase	Breast cancer	Promote cell proliferation	(80)
	0041732	GLI4 expression		Reduce apoptosis
	circRNA-	Bind to miR-579-3p/increase GLI2	Hepatocellular carcinoma	Promote the proliferation, inhibit	(81)
	0036412	expression		cell cycle arrest
	circRNA-	Sponge miR-338-3p/increase GLI2	Prostate cancer	Promote tumor proliferation-	(82)
	0070512	expression		migration
microRNAs	miR-182-5p	Reduce GLI2 expression	Lung adenocarcinoma	Promote tumor colony formation	(83)
				ability
		Bind to FOXF2, downregulate	Bladder cancer	Promote proliferation and	(84)
		FOXF2 and activating the SHH		migration
		pathway
	miR-212	Reduce PTCH1 expression	Non-small cell lung cancer	Promote tumor proliferation,	(85)
				migration, and invasion
	miR-378	Increase SUFU expression	Non-small cell lung cancer	Promote tumor migration,	(86)
				invasion, and angiogenesis
	miR-7-5p	reduce SMO expression	Gastric cancer	Reduce tumor colony formation	(87)
				ability, and invasion
	miR-194	reduce SUFU expression	Gastric cancer	Promote tumor proliferation and	(88)
				migration
	miR-150	reduce SUFU expression	Gastric cancer	Promote tumor proliferation,	(89)
				migration, and EMT
	miR-324-3p	reduce GLI3 expression	Nasopharyngeal carcinoma	Reduce EMT, tumor proliferation,	(90)
				invasion, and metastasis
				Promote apoptosis
	miR-324-5p	Reduce SUFU expression	Gastric cancer	Promote tumor proliferation,	(91)
				migration, and colony formation
		Reduce GLI1 expression	Glioma	Reduce tumor proliferation	(92)
		Reduce GLI1 expression	Ovarian cancer	Reduce tumor proliferation	(93)
		Reduce SMO, GLI1 expression	Multiple myeloma	Reduce tumor growth, survival	(94)
				and stem cell compartment
		Reduce SMO expression	Multiple myeloma	Reduce tumor growth	(95)
	miR-20b	Reduce SUFU expression	Gastric cancer	Promote tumor proliferation,	(96)
				migration, and EMT
	miR-423-5p	Reduce SUFU expression	Gastric cancer	Promote tumor proliferation,	(97)
				migration, and metastasis
	miR-30c-2-3p	Reduce Ras-related protein in	Gastric cancer	Reduce tumor proliferation	(98)
		brain 31 (RAB31) and GLI1		Promote apoptosis
		expression
	miR-873-5p	Reduce GLI1 expression	Gastric cancer	Reduce tumor viability	(99)
				Promote apoptosis
	miR-338	Reduce KIF1A expression	Pediatric neuroblastoma	Promote tumor apoptosis	(100)
				Reduce tumor growth
	miR-338-3p	Reduce SMO expression	Colorectal cancer	Reduce tumor proliferation,	(101)
				invasion, migration
				Promote apoptosis
	miR-330-5p	Reduce SMO expression	Hepatocellular carcinoma	Reduce EMT, tumor proliferation,	(11)
				migration, invasion, and stemness
	miR-132	Reduce SHH expression	Pancreatic cancer	Promote tumor proliferation	(102)
				Reduce apoptosis
	miR-326	Reduce SMO expression	Glioma	Reduce tumor proliferation and	(103)
				stemness
			Osteosarcoma	Reduce tumor proliferation,	(104)
				invasion, tumor growth, and
				metastasis
			Chronic myeloid leukemia	Reduce tumor proliferation	(105)
				Promote apoptosis
			B-cell acute lymphoblastic	Reduce ABCA3 expression	(106)
			leukemia	Promote multidrug resistance
		Increase GLI1 expression	Glioblastoma	Reduce tumor proliferation and	(107)
				migration, promote apoptosis
		Reduce SMO and GLI2 expression	Medulloblastoma	Reduce tumor proliferation, self-	(108)
				renewal, and stemness
	miR-9	Reduce PTCH1 expression	Glioblastoma	Reduce ABC transporters	(109)
				Promote temozolomide resistance
	miR-129-5p	Reduce SHH, GLI1 and GLI2	Cervical cancer	Reduce tumor proliferation,	(110)
		expression		invasion, migration, angiogenesis
	miR-584	Reduce GLI1 expression	Cervical cancer	Reduce tumor proliferation,	(111)
				migration, and invasion
				Promote apoptosis
	miR-218	Reduce GLI1 expression	Prostate cancer	Reduce tumor migration, EMT and	(112)
				stemness
		Reduce GLI3 expression	Cervical cancer	Reduce tumor proliferation and	(113)
				apoptosis
	miR-506	Reduce GLI3 expression	Cervical cancer	Reduce tumor proliferation and	(114)
				chemoresistance
				Promote apoptosis
	miR-202	Reduce GLI2 expression	Osteosarcoma	Reduce tumor proliferation	(115)
				Promote apoptosis
	miR-1271	Reduce SMO expression	Multiple myeloma	Reduce tumor proliferation	(116)
				Promote apoptosis
	miR-7-5p	Reduce GLI3 expression	Bladder cancer	Reduce tumor proliferation,	(117)
				migration and EMT
	miR-224	Reduce SUFU expression	Bladder cancer	Promote tumor growth and	(118)
				invasion
	miR-361-3p	Reduce GLI1 and GLI3 expression	Retinoblastoma	Reduce tumor proliferation and	(119)
				stemness
	miR-29-a-3p	Reduce FEM1B and GLI1	Colorectal cancer	Promote oxaliplatin resistance	(120)
		expression
	miR-142-3p	Reduce TP53INP2 expression/	Colon Cancer	Promote tumor proliferation	(121)
		activate HH pathway		Reduce apoptosis
	miR-361-3p	Reduce GLI1 expression/activate	Prostate cancer	Promote EMT and tumor	(122)
		AKT/mTOR signaling pathway		metastasis
	miR-326	Reduce SMO expression	Cervical squamous cell	Promote radiation sensitivity	(123)
			carcinoma
		Reduce SMO expression	Pancreatic ductal adeno-	Reduce tumor metastasis and	(124)
			carcinoma	angiogenesis
	miR-378a-3p	Reduce GLI1 and GLI2 expression	Gastric cancer	Reduce tumor stemness	(125)
	miR-221-3p	Target FOXP2/activate HH	Thyroid cancer	Promote tumor proliferation, cell	(126)
		pathway		sphere-formation ability
				Promote apoptosis
	miR-361-5p	Reduce GLI1 expression	Colorectal cancer	Reduce tumor stemness	(127)

[i] HH, Hedgehog; EIF5A, eukaryotic translation initiation factor 5A; PTCH, Patched; DYNC1I2, dynein cytoplasmic 1 intermediate chain 2; CELF2, CUGBP elav-like family member 2; GLI, glioma-associated oncogene; SUFU, suppressor of fused protein; SHH; sonic HH; IGF2BP, insulin like growth factor 2 MRNA binding protein 1; FBXW1, beta-transducin repeat containing E3 ubiquitin protein ligase; SMO, Smoothened; EMT, epithelial-mesenchymal transition; miR, microRNA; Lnc, long non-coding; GAS1, growth arrest specific 1; MALAT1, metastasis associated lung adenocarcinoma transcript 1; WDR5WD repeat domain 5;MLL3, lysine methyltransferase 2C;P300, E1A binding protein P300; H3K4, lysine methyltransferase 2A; METTL3,methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit; HNRNPC, heterogeneous nuclear ribonucleoprotein C; STAT3, signal transducer and activator of transcription 3; CEP85, centrosomal protein 85; FUS, FUS RNA binding protein; FOXF2, forhead box F2; RAB31, RAB31 member RAS oncogene family; KIF1A, kinesin family member 1A; ABCA3, ATP binding cassette subfamily A member 3; FEM1B, fem-1 homolog B; TP53INP2, tumor protein P53 inducible nuclear protein 2.

Tumor-promoting inflammation

HH and Helicobacter pylori (Hp) infection

The HH pathway mechanism in tumor-promoting inflammation can be exemplified by Hp infection, which has been proven to be associated with gastric cancer. Once infected, Hp injects cytotoxic associated gene A into gastric cells, resulting in the accumulation of bone marrow cells in the stomach following the secretion of SHH ligands by parietal cells. Then, these cells differentiate and mature under the induction of factors such as IFN-α, express GLI1-dependent schlafen 4 and secrete interleukin (IL)-1β to activate the IL-6/phosphorylated signal transducer and activator of transcription (STAT)-3 pathway. The activation of SHH during Hp infection was closely related to the expression of programmed death-ligand 1 (PD-L1) (128), as well as the emergence of myeloid-derived suppressor cells (MDSCs), intestinal metaplasia and soluble polypeptide expression metaplasia (129).

HH and chronic liver injury

The relationship between hepatocellular carcinoma and the HH pathway activated by chronic liver injury has also been clarified. Specifically, hepatitis B virus X protein has been revealed to directly interact with GLI1 and promote disease progression when GLI2 is not inhibited by Sestrin 3 (130).

HH and other tumor-promoting inflammation

In pan-cancer, activation of the transcriptional programs of SHH in the non-T cell-inflamed tumor microenvironment was discovered in a study by Bao et al (131), after performing an unbiased genome-wide pathway discovery. Furthermore, non-classical HH activation can promote tumor development by generating pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, IL-1β (132) and TGF-β (133), in hypoxic or inflammatory environments. In addition, hypoxia also contributes to the enrichment of immunosuppressive cells (134), as well as the excessive activation of the Notch/HH axis (135). Notably, STAT is one of the main factors of pro-inflammatory signal transduction. The interaction between STAT and HH is an important component of inflammation and tumor promotion mechanisms (136). In basal cell carcinoma, IL-6 has been revealed to cooperate with carcinogenic HH/GLI signaling via the IL-6R/Janus kinase 2/STAT3 pathway (137). In addition, the antitumor effect of IFN-γ/STAT1 can be antagonized by the activation of suppressor of cytokine signaling 1 by GLI1 and GLI2 (138).

HH and anti-inflammation

By contrast, the anti-inflammatory effect of HH pathway activation is also a protective mechanism, particularly in acute inflammation. Increased expression of the anti-inflammatory cytokine, IL-10, in HH pathway-responsive stromal cells and concomitant increases in CD4 forkhead box (Fox)p3 regulatory T cells (Tregs) reduces the tumor burden of colitis-associated colon cancer (139). Similarly, the pancreatic gland is also protected from acute pancreatitis by the SHH/GLI1/IL-10 axis (140). When considering that the HH pathway is also involved in the interference of cell differentiation and maturation during tissue repair following inflammation (141), whether to administer pathway inhibitors in the early stages of inflammation and the risk of tumor development remain to be considered.

Avoiding immune destruction

However, while activation of the HH pathway induces anti-inflammatory effects, another real problem emerges: Tumor immune escape (142). In fact, there is a complex crosstalk between immune cells, cancer cells and inflammation.

HH and tumor-associated macrophages (TAMs)

In most tumors, fibroblasts, endothelial cells and macrophages exhibit strong positive connections with GLI (143). In previous studies, TAMs derived from MDSCs were revealed to secrete a variety of anti-inflammatory cytokines and express immune checkpoint ligands that inhibit effector T cells and recruit Tregs (144,145). Research thus far has mainly focused on the association of TAM aggregation with abnormal expression of SHH and activation of HH/GLI (146–148). With the participation of krüppel-like factor 4 SHH-derived TAM M2 polarization (149), and GLI1 can directly affect the M2 activation state by activating the feedforward loop of STAT6-IL-4ra (150). In addition, the STAT3 pathway has also been revealed to be involved in the regulation of PD-L1 expression in TAMs by tumor-derived SHH ligand (151,152). The carcinoma cell-TAM-carcinoma cell loop may produce a hierarchical amplification effect via the SHH/GLI2-TGF-β1 loop, promoting tumor growth (153). By targeting tumor-supportive M2-like TAMs, a synergistic effect of peroxisome proliferator activated receptor γ with SMO has also been proven (146).

HH and regulatory cells

In an infectious state, GLI1 directly increases the transcription of cyclooxygenase-2/prostaglandin E2 and regulates miR-324-5p and miR-338-5p. These miRNAs target PD-L1 to increase its expression, finally realizing the SHH/phosphoinositide-3 kinase (PI3K)/mTOR/NF-κB signal transduction of dendritic cells and activating Treg amplification (154). In gastric cancer, this process was discovered to be mediated by the mTOR signaling pathway, involving the SMO-independent HH pathway (145). In addition, blocking HH reprogramed Treg trans-differentiation into inflammatory Th17 cells, which enhanced the recruitment of cytotoxic CD8+ T cells into tumors (155).

HH and immune checkpoint inhibitors

HH activity detection can be used to predict the efficacy of immune checkpoint inhibitors, with the support of clinical data (156,157). The expression of programmed death protein-1 (PD-1)/PD-L1 induced by various pro-inflammatory factors changes under the crosstalk of HH and other pathways (147,158,159). The high prevalence of Tregs within the tumor microenvironment and induction of PD-1/PD-L1 is likely to constitute a major mechanism of immunosuppression by HH/GLI signaling in cancer (147). These findings increase the therapeutic opportunities for combination treatments with HH and immune checkpoint inhibitors.

Enabling replicative immortality and sustaining proliferative signaling

HH and human telomerase reverse transcriptase (hTERT)

In the unlimited proliferation of tumors, telomerase determines the replication potential of cancer cells. Research has revealed that hTERT is a direct target of HH/GLI, and the effect on hTERT activity is related to differentiating benign and malignant tumors (160). Reduced cell proliferation and GLI1 levels have also been observed in cancer cells with long-term use of telomerase inhibitors (161). However, it cannot be concluded that TERT forms a feedback loop with HH, since the current suggestion is that TERT upstream of HH is more likely to activate the HH pathway by regulating miRNA (162) and recruiting pro-oncogenic transcription factors (163). These effects contribute to increasing invasion and are independent of changes in telomerase activity.

HH and cell cycle regulation

Regulation of the tumor cell cycle is mainly dependent on two important pathways: The RB transcriptional corepressor 1 and p53 pathways. Furthermore, mutations in these two pathways lead to the formation of primary cilia, abnormal elevation of Hedgehog ligands (164,165) and direct regulation of downstream cell cycle regulators, such as cyclin (166) and CDKs (167). It mediates HH-induced DNA replication. This was also partially dependent on the PI3K/AKT pathway (167). The HH pathway has also been revealed to block its inhibition of cyclin regulation by affecting stem cell-related factors, such as BMI-1, to inhibit the downstream p14 and p16 proteins (168). Another well-known cell cycle regulator is FoxM1. GLI1 has been demonstrated to bind to FoxM1 and initiate the effect of Xenopus kinesin-like protein 2 on cell division (169). The crosstalk between the Notch pathway as a proliferation-related pathway and the HH pathway also decreases G1/G0 cycle retardation (170).

Resisting cell death and evading growth suppressors

HH and TNF-related apoptosis-inducing ligand (TRAIL)

The HH pathway has been implicated in regulating apoptosis. TRAIL has become a new target for cancer treatment due to reduced toxicity to normal tissues and specificity for tumor cell apoptosis. The positive crosstalk between NF-κB and the HH pathway amplifies the effect of resistance to TRAIL-related apoptosis (171,172). However, blockade of the GLI family increases TRAIL sensitivity (173).

HH and the B-cell lymphoma-2 (Bcl-2) family

A considerable number of studies have revealed that the Bcl-2 family are target genes of the HH pathway, including BCL-2 (174), myeloid cell leukemia-1 (174,175), BCL-XL (174) and NOXA (176), which play an anti-apoptotic role by blocking the activity of the caspase family, leading to TRAIL resistance. Bcl-2 proteins also form a feedforward signal with SUFU to further induce the expression of target genes in the HH pathway (174). Accordingly, inhibition of the HH pathway provides a new avenue for the treatment of TRAIL-resistant tumors.

HH and the MYC family

Among the apoptotic pathways, the MYC family (oncogenes related to apoptosis) also closely interact with HH. Upregulation of the family member protein, MYCN, in basal cell carcinomas is a key factor that re-activates dormant HH signals and induces tumor progression (177). Similarly, MYCN has been identified as an invasive marker in neuroblastoma, which was associated with HH signaling, for determining prognosis. Although the positive or negative correlation between GLI1 expression and prognosis in neuroblastoma remains controversial, most evidence suggests that high GLI1 expression indicates an improved prognosis in MYCN-amplified neuroblastoma (178). An explanation for this is that protein kinase-like endoplasmic reticulum kinase-EIF2α pathway is an important mediator in Hh-dependent autophagy on MYCN-amplified neuroblastoma (179).

HH and other cell death pathways

In addition to TRAIL and the MYC family, the anti-apoptotic effects of other apoptosis-related factors also depended on HH. For instance, TNF-α induces the expression of activator protein 1 family members and regulates apoptosis through the HH pathway (180,181). Survivin, another inhibitor of apoptosis family, has been revealed to be a transcriptional target of GLI (182). HH/GLI1 signaling mediates the RNA polymerase III signaling pathway and tRNA synthesis to regulate the cell cycle and death receptor binding (183).

It is worth noting that the effect of HH-induced autophagy on apoptosis does not act alone in various cancer types. On the one hand, HH-induced autophagy leads to cell death and affects a variety of cancer types by regulating targets such as BCL-2 interacting protein 3 and LC3 II (184,185). Correspondingly, certain drugs have been revealed to induce autophagy and cell death by blocking HH signaling (186,187). On the other hand, HH-induced autophagy can also promote tumors by providing energy for tumor development. SHH inhibition in thyroid cancer activates TAK1, phosphorylates JNK/AMPK and induces autophagy (181). Therefore, acknowledging the effect of autophagy on apoptosis caused by inhibition of HH can guide the usage of drug combinations more reasonably.

In addition to systematic apoptosis pathways, another phenomenon, dependence receptors triggering apoptosis signals without ligands, have been gradually recognized. Autocrine SHH interference in colon, pancreatic and lung cell lines triggers cell death via PTCH proapoptotic signaling (188). The cell-adhesion molecule-related/downregulated by oncogenes protein and its ligand, SHH, perform identically (189). However, very little optimization work has been conducted on this finding.

HH and radio resistance

In addition to interfering with apoptosis, HH has also been implicated in resistance to cell death induced by physical and chemical factors (166). Under radiation, HH is upregulated, which may be driven by TGF-β and TNF-α (190) and mediated by mTOR/ribosomal protein S6 kinase β-1 (191). Atypical protein kinase Cι/λ and GLI can also form a positive feedback loop under high levels of radiation to change the radiosensitivity of tumors (192). In addition, the HH pathway activated by chemoradiotherapy also increases the rate of tumor proliferation by upregulating the G1/cyclin/Rb axis (193). In response to irradiation, GLI1 activates RNA polymerase I, which synthesizes ribosomal RNA for accommodating cell proliferation and division (194). Thus, blocking HH signaling was demonstrated to be an effective method for inhibiting accelerated tumor repopulation following therapy.

Senescent cells

The HH pathway is also associated with cell senescence-related diseases. For instance, IHH protects bone marrow-derived mesenchymal stem cells from senescence-associated secretory phenotype (SASP)-induced senescence by downregulating the ROS/mTOR pathway during oxidative stress (195). However, recent studies have gradually recognized that SASP has a bidirectional regulatory effect on tumors and may be related to the degree of aging load (196). In medulloblastoma, a PTCH1 loss of heterozygosity was discovered to be associated with high levels of cellular senescence before tumor occurrence. However, other subsequent spontaneous site mutations, such as in p53, stimulate inhibition of senescence and promote tumor development by modulating CDKs (197).

Activating invasion and metastasis

HH and hypoxia-induced epithelial-mesenchymal transition (EMT)

Hypoxia is a mechanism underlying tumor invasion and metastasis that is partially achieved by activating the HH pathway. Hypoxia is often accompanied by TNF, NOX4 and other products. TNF-α can upregulate the expression of GLI1 via NF-κB transcription to achieve EMT and drug resistance (132). Furthermore, NOX4 expression triggers the reactive oxygen species-mediated non-canonical HH pathway in the initiation of EMT (198). Hypoxia inducible factor (HIF) is also a widely studied regulator. The upregulation of HIF-1α was revealed to be associated with the upregulation of SHH ligand secretion and GLI1 expression, thereby increasing metalloproteinase (MMP) expression and EMT progression (199,200). It should be noted that activation of the HH pathway during hypoxia leads to an increase in stromal fibroblasts, then the deposition of fibrous tissue and ultimately the aggravation of hypoxia (201). Hypoxia can also provoke HIF-2α to induce GLI1 activation through a SMO-independent pathway (202), which can be ablated by PI3K inhibitor or MEK inhibitor (202). This finding also suggests a complex connection between these pathways.

HH and the PI3K pathway in metastasis

The crosstalk between the HH, PI3K and MEK pathways has been gradually clarified. Previously, there was evidence that fibroblast metastasis required the stimulation of Ras homolog family member (Rho)A by SMO, which can be realized by a heterotrimeric Gi proteins/PI3K/Rac1 series of activations (7). Subsequently, it was revealed that the PI3K/AKT/mTOR pathway plays an important role in SHH signaling to promote metastasis (203). More specifically, AKT/GSK3β signaling mediates the upregulation of GLI1 expression, thereby obtaining epithelial mesenchymal plasticity (204). In addition, astrocyte elevated gene-1 protein is induced by PI3K/AKT signaling and is vital in the metastasis and development of various types of cancer. Therefore, it was not surprising that PI3K pathway is involved in the crosstalk process (205).

HH and the MEK pathway in metastasis

In the MEK pathway, GLI1 directly binds to the promoter region of the CXCR4 gene and participates in stimulated signal transduction of CXCL12 to stimulate the phosphorylation of ERK (206). This is consistent with the observation that HH upregulates MMP-9 expression via the ERK pathway (207), while MEK/ERK signaling is involved in the regulation of GLI1 activity in turn (208,209). Furthermore, the MEK/AKT pathway could be regulated by RAS and others. The widespread occurrence of this regulation in cancer cells rectifies the singleness of the HH pathway, which is mainly activated in the microenvironment but not tumor cells (208,209). The close relationship between these three pathways supports the notion that the synergistic role could be amplified by blocking the pathways simultaneously (210).

HH and the Wnt/β-catenin pathway in metastasis

The HH and Wnt/β-catenin pathways have also been demonstrated to impose a synchronized regulation on tumor metastasis. In fact, a crosstalk between these pathways does exist (89,211). During the development of cancer associated fibroblasts (CAFs), two pathways regulate the target gene of TGF-β/SMAD3 to participate in the EMT process (212). Although uncertainty remains as to the specific mechanism, it is not difficult to observe that tumor invasion and metastasis are the ultimate outcome of multiple pathways.

GLI1 and variants as key targets in metastasis

In the previous section, the upstream and downstream molecular mechanisms of GLI1 were briefly mentioned. In gastric cancer, galectin-1 from CAFs binds to β1 integrin and targets GLI1 to promote both EMT and vasculogenic mimicry (213). Signal peptide CUB EGF-like domain-containing protein 2 (214) and FoxF1 (215) both regulate tumor metastasis via GLI1. In addition, S100A4 is a newly discovered downstream target gene of GLI1 (216). However, a new theory suggests that tumor progression is dynamically regulated between proliferation and metastasis through up and downregulated GLI1 levels, rather than just upregulated GLI1 alone. Moreover, endogenous GLI1 can directly bind to the promoter of the E-cadherin gene, termed CDH1, and resist EMT (217).

Compared with GLI1, truncated GLI1 (tGLI1) demonstrated a stronger association with abnormal HH signals. In addition to regulating the known GLI1 target genes in the crosstalk with STAT3 and other pathways (218), tGLI1 can also regulate the expression of genes that were not regulated by GLI1, including vascular endothelial growth factor (VEGF) and heparinase (219). Moreover, tGLI1 displays a strong correlation with tumor metastasis. The presence of tGLI1 enhances the expression of MMP-2 and MMP-9 and may target twist and snail (220). In addition, tGLI1 has been identified as a brain metastasis-promoting transcription factor in breast cancer (221). tGLI1 increases the degree of cancer cell stemness by upregulating genes such as Nanog and by activating astrocytes to achieve metastasis (219). In summary, it is hypothesized that tGLI1 is more likely to be a marker for the diagnosis and prognosis of cancer metastasis, and thus may become a new therapeutic target (222).

With the accumulation of research, the unknown role of ncRNA in EMT progress and MMP expression has been gradually uncovered (Table II).

Inducing accessing vasculature

The main current view is that the effect of the HH pathway on angiogenesis ultimately depends on the interaction with the VEGF pathway. Previously, some scholars proposed the existence of a HH interacting protein/HH/VEGF/Notch signaling axis, but the role of GLI1 in this process has gradually been revealed. In a tissue microarray analysis (223), GLI1 was linked to the upregulation of VEGF receptor 2 (VEGFR2).

Another view is that tGLI1 is a direct participant in the VEGF pathway instead of GLI1, and that tGLI1 also inhibits the expression of soluble VEGFR2, the thrombospondin family and TIMP metallopeptidase inhibitor 2 (223,224). These molecules are considered to be potent antagonists of angiogenesis or lymphangiogenesis. In the presence of VEGF, Rho GTPases are also targets of the SHH non-classical pathway (225). In addition, the crosstalk between mTOR and the HH pathway in angiogenesis is an area of interest (226). It was previously demonstrated that the SMO-independent activation of GLI1 could be mediated by the mTOR/S6K1 pathway, blocking the interaction between SUFU and GLI1 (227,228), while also upregulating VEGF (229). In addition, cysteine-rich protein 61 is considered to be another angiogenic target of SHH/GLI1 (211).

Following further research of the basic pathway, it may be effective to inhibit angiogenesis and reduce the relative area of tumor blood vessels by using HH inhibitors or by combining with an mTOR pathway inhibitor after evaluating the expression of HH, to reduce drug resistance (225,230). In contrast to expectations, it has been demonstrated that SHH-deficient pancreatic ductal adenocarcinoma showed higher vascular density and proliferation activity, and its response to anti-angiogenesis therapy was more notable (231). A possible explanation for this is that the inhibition of HH may lead to lower differentiation. Taken together, the application of HH inhibitors with anti-angiogenesis therapy requires further attention.

Dysregulating cellular metabolism

HH and glycolysis

The Warburg effect has been widely discussed in terms of tumor metabolic changes. This effect allows cells to replace the mechanism of oxidative phosphorylation with aerobic glycolysis, thereby obtaining more energy to promote tumor development. The HH pathway mediates the Warburg effect of tumor cells and CAFs. Caveolin-1 (Cav-1) is present in the tumor matrix and participates in the regulation of glycolytic activity (232). The deletion of Cav-1 is associated with high expression levels of GLI1 (233). It was also revealed that the activation of SMO promotes glycolysis via GLI upregulation and the AMPK-mediated activation of hexokinase 2 and pyruvate kinase 2 (234).

In addition, HH activity is involved in the regulation of metabolism and bioenergy in TAMs. Inhibition of HH causes metabolically demanding M2 macrophages to shift their metabolism and bioenergetics from fatty acid oxidation to glycolysis (148). HH signaling also acts downstream of metabolic reprogramming to influence tumorigenesis. HH signaling mediates the hyperglycemia inducing glycolytic phenotype and promotes EMT via Yes-associated protein 1 (235).

HH and other metabolism

Ornithine decarboxylase (ODC)1 is aberrantly upregulated in primary (SHH subtype) medulloblastoma, which increases polyamine metabolism to promote tumors (236). In this instance, AMPK promotes the stable formation of the SUFU/CCHC type nucleic acid binding protein (CNBP) complex via phosphorylation of CNBP, and further promotes the expression of ODC (237). In addition, a metabolic switch to oxidative phosphorylation was revealed to be promoted by GLI1 editing (238).

Drugs that regulate the HH pathway

HH inhibitors

The use of HH pathway inhibitors as anticancer drugs has gained significance. At present, five HH pathway inhibitors have been approved for marketing. A large number of new generation inhibitors and drugs targeting new targets have entered clinical trials. Among them, SMO inhibitors are classic inhibitors as inhibition of SMO is a reliable route to blocking activation of the HH pathway. However, the frequent occurrence of drug-resistant mutations in SMO means that traditional SMO inhibitors are prone to failure, a problem that requires urgent attention. Second-generation SMO inhibitors have been proven to be effective in preclinical experiments by targeting specific SMO site mutations or by improving the binding affinity. Directly targeting the downstream signals is another traditional solution. The HH inhibitor drugs are summarized in Table III.

Table III.

Hedgehog inhibitor drugs.

Table III.

Hedgehog inhibitor drugs.

Drugs	Indications	The world's highest Research and Development stage	Target
Vismodegib	Advanced solid tumors/basal cell carcinoma/fallopian tube carcinoma/head and neck tumors/metastatic breast cancer/metastatic ovarian cancer/odontogenic tumor/peritoneal tumor	Marketing authorization	Hedgehog protein/SMO
Glasdegib	Acute myeloid leukemia/glioblastoma	Marketing authorization	SHH/SMO
Sonidegib	Advanced solid tumors/basal cell carcinoma/basal cell nevus syndrome	Marketing authorization	Hedgehog protein/SMO
Arsenic trioxide	Acute myeloid leukemia/acute promyelocytic leukemia/gliomas	Marketing authorization	GLI
Itraconazole	Aspergillus infection/basal cell nevus syndrome/bacillus infection/malignant tumor/fungal infection/histoplasma infection/hormone-resistant prostate cancer/metastatic non-small cell lung cancer/prostate cancer	Marketing authorization	SMO (cilial translocation inhibitor)
Patidegib	Basal cell nevus syndrome	Phase III	Hedgehog protein/SMO
Taladegib	Advanced solid tumors/malignant tumor/idiopathic pulmonary fibrosis/interstitial lung disease	Phase II	SMO
NLM-001	Adenocarcinoma/metastatic pancreatic cancer/pancreatic tumor	Phase II	Hedgehog protein
2S,4R-itraconazole	Advanced solid tumors/basal cell carcinoma/non-small cell lung cancer	Phase II	Hedgehog protein
GT-1708	Acute Myeloid Leukemia/basal cell carcinoma/breast tumor/gastrointestinal stromal tumor/blood tumor/idiopathicpulmonary fibrosis/leukemia/lung cancer/myelodysplastic syndrome/prostate cancer	Phase II	Hedgehog protein/SMO
BMS-833923	Leukemia/stomach neoplasms/esophageal neoplasms/small cell lung carcinoma	Phase II	SMO
ZSP-1602	Basal cell carcinoma/malignant tumor/esophageal tumor/glioblastoma/brain medulloblastoma/neuroendocrine tumor/small cell lung cancer/gastric tumor	Phase I	SMO
IMP-5471	Malignant tumor/hematological malignancies/idiopathic pulmonary fibrosis	Clinical trial application	Hedgehog protein
TDI-3410	Pancreatic tumor	Preclinical study	Hedgehog Acyltransferase
RU-SKI 43 hydrochloride	Malignant tumor	Preclinical study	Hedgehog Acyltransferase
SLT-0463	Rhabdomyosarcoma	Preclinical study	Hedgehog protein
Oxy-210	Skin diseases/fibrosis/liver fibrosis/nonalcoholic steatohepatitis/non-small cell lung cancer/pancreatic disease/pancreatic tumor/pulmonary fibrosis	Preclinical study	Hedgehog protein
CEP-1430	Pancreatic tumor	Preclinical study	SHH
Robotnikinin	Malignant tumor	Preclinical study	SHH
Deuterated vismodegib analogs	Malignant tumour	Preclinical study	Hedgehog protein
PF-05274857	Malignant tumor	Preclinical study	SMO/SHH
Jervine	Malignant tumor	Preclinical study	SMO/SHH
Ciliobrevin D	Malignant tumor	Preclinical study	SMO/SHH
Nilotinib	Brain medulloblastoma	Preclinical study	Hedgehog protein/SMO
ABT-199	Malignant tumor	Preclinical study	SMO
DCBCO-1303	Malignant tumor	Preclinical study	SMO
Oxy-186	Lung cancer/pancreatic ductal adenocarcinoma	Preclinical study	SMO
Cyclopamine	Malignant tumor	Preclinical study	SMO
LEQ-506	Malignant tumor	Preclinical study	SMO
SANT-1	Malignant tumor	Preclinical study	SMO
MRT-10	Malignant tumor	Preclinical study	SMO
MRT-81	Malignant tumor	Preclinical study	SMO
MK-4101	Malignant tumor	Preclinical study	SMO
ZINC12368305	Malignant tumor	Preclinical study	SMO
HH-101	Malignant tumor/metastatic carcinoma/solid tumor	Preclinical study	GLI1/SMO
SR-38832	colorectal cancer	Preclinical study	GLI1
Glimidazole derivates	Malignant tumor	Preclinical study	GLI1
GANT61	Malignant tumor/multiple sclerosis	Preclinical study	GLI1
JK184	Malignant tumor	Preclinical study	GLI1
VAR-101	Basal cell carcinoma/non-small cell lung cancer/squamous cell carcinoma	Preclinical study	GLI1
Ciliobrevin A (HPI-4)	Malignant tumor	Preclinical study	GLI

[i] SMO, Smoothened; GLI, glioma-associated oncogene; SHH, sonic Hedgehog.

Post-resistance treatment strategy

HH pathway mutations have been revealed to be associated with enhanced tumor immunogenicity, and it may be feasible to further seek immune checkpoint inhibitor treatment for greater benefits (239). SMO resistance can also be prevented by altering the epigenetic changes of histones or transcription factors GLI1 and GLI2, such as by HDAC (240). Moreover, new technologies such as CRISPR/Cas9 for pathway site-specific gene editing are also being developed (241), which may pave the way for HH therapies. Although drugs for downstream targets are under study, progress has been slow (242), which may be partly due to downstream signals, such as GLI1, being activated by other pathways, such as the TGF-β, Ras and PI3K/AKT pathways. Therefore, blocking the activity of non-classical pathways is also being considered as a new alternative strategy (243).

Drugs targeting ncRNA should also be considered as a future direction for HH pathway-related treatment. However, how to narrow the scope of the best target ncRNAs and how to improve recognition of the structure of ncRNA remains to be solved.

Natural drugs the regulate the HH pathway

As aforementioned, a variety of anti-HH/GLI drugs have been developed. However, the complex crosstalk between pathways, compensatory mechanisms, the generation of primary or secondary drug resistance, as well as toxic side effects, may still lead to the failure of current drugs. Recently, natural drugs with multiple targets and a higher safety profile have attracted attention. The combination of natural drugs and anticancer drugs has been revealed to be more effective than anticancer drugs alone. In Table IV, the new progression of some natural components and their main targets and effects in research, which may provide support for the future transformation of natural drugs based on the HH pathway into anticancer drugs, are summarized.

Table IV.

Main targets and effect of Natural drug compound in the inhibition of Hedgehog signing pathway.

Table IV.

Main targets and effect of Natural drug compound in the inhibition of Hedgehog signing pathway.

Natural compound	Origin	Main targets	Cancer types
Berberine (BBR)	Berberis species plants	SMO, SHH	Prostate cancer, colon cancer, lung cancer, nasopharyngeal cancer, breast cancer, and leukemia
Ethanol Extract of Scutellaria barbata D Don (EESB)	Scutellaria barbata D. Don	VEGF-A	Colorectal cancer
Ethanol Extract of Hedyotis diffusa Willd (EEHDW)	Hedyotis diffusa Willd	SHH, PTCH-1, SMO, GLI1, VEGF-A, VEGF-2	Colorectal cancer
Genistein	Soy products	SMO, GLI1	Breast cancer
Sutherlandioside frutescens methanol extract (SLE, Sutherlandioside D is the most potent compound)	Sutherlandia frutescens	GLI1, PTCH-1, Hsd11b1, Penk	Prostate cancer, cervical carcinoma, breast cancer
Sulforaphene	Cruciferous vegetables such as broccoli and cabbage	GLI1, SMO	Breast cancer, ovarian cancer
Tea polyphenols Epigallocatechin	Green tea catechin	GLI1, SMO, PTCH-1	Tongue and liver cancer
Gallete (EGCG) and Theaflavin (TF)
Curcumin	Rhizomes of Curcuma longa	SHH, SMO, SUFU, GLI1, GLI2	Lung cancer, pancreatic cancer
Graviola leaf and stem extract (GLSE)	Graviola	SMO, GLI1/2, SUFU	Non-melanoma skin cancers
Bufalin (BF)	Chansu	Smo, GLI1	Liver cancer
Cordycepin	Cordyceps militaris	SMO, PTCH, GLI1/2	Non-small cell lung cancer
Silymarin	The fruits of Silybum marianum	SMO	melanoma, malignant skin cancer
Moringa oleifera methanolic leaves extract	Moringa oleifera	GLI1, SMO	Prostate cancer
Inoscavin A	Sanghuangporus vaninii extract	SHH, PTCH-1, SMO, GLI1	Colon cancer
Crocetin	Saffron stigma	SHH, VEGF	Gastric cancer
Resveratrol	Plant-derived bioactive nutrient (grapes, red wine, multi-berries, peanuts)	SMO	Renal cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, colorectal cancer
Withaferin A	Withania somnifera	GLI1	Pancreatic cancer, prostate cancer, breast cancer
Caralluma europaea Extract (CEE)	Caralluma europaea	Caspase-3	Pancreatic cancer
Methanol extract of Adenium obesum	Adenium obesum	PTCH, Bcl-2	Pancreatic cancer
Amentoflavone	Biophytum sensitivum and Selaginella species and Chamaecyparis obtusa	GLI1	Breast cancer
Zerumbone	Subtropical ginger Zingiber zerumbet	GLI1, CXCR4	Breast cancer
Edunin	Azadirachta	PTCH, SMO, GLI1, SHH, SUFU	Pancreatic cancer cells

[i] SMO, smoothened; SHH, sonic Hedgehog; PTCH, Patched; GLI, glioma-associated oncogene; Hsd11b1, hydroxysteroid 11-beta dehydrogenase 1; SUFU, suppressor of fused protein; Bcl-2, B-cell lymphoma/leukemia 2; CXCR4, C-X-C motif chemokine receptor 4.

Conclusions

Through combing the mechanisms of the HH pathway in different tumor phenotypes, it is not difficult to recognize the notable role of the HH pathway in tumor formation. The interaction between HH pathway factors forms several negative feedbacks in cell function such as promoting autophagy apoptosis, and positive feedbacks such as the feedback between hypoxia and angiogenesis. Knowledge of HH pathway signal transduction, the crosstalk mechanisms and the influence on phenotype may improve the clinical vigilance of anomalous HH-related test results. Moreover, it may assist the more accurate use of drugs in tumor treatment and provide more therapy strategies.

However, the shortcomings in the present study review of the HH pathway remain undeniable. A common problem is the lack of accurate methods to clarify the mechanisms of specific factors in the complex crosstalk of pathways for tumor metastasis. The exploration of positive and negative regulation of the HH pathway in different cancer types is also limited. Moreover, further study is needed to correlate expression of the HH pathway with tumor characteristics, such as source, metastasis rate, recurrence rate and other prognosis factors, by referring to HH gene status. In this way, accurate stratification of tumor subtypes can be achieved, which is also the mainstream direction of future oncology development. In terms of drugs, there has been an upsurge in the field of natural medicines based on HH pathway treatment. However, very little information is available in the systematic summary of research progress in this area. Improved understanding of the HH pathway may assist with improving clinical treatment by solving the aforementioned problems.

Supplementary Material

Supporting Data

Acknowledgements

Not applicable.

Funding

The present study was supported by the Zhejiang Provincial Natural Science Foundation of China (grant no. LQ22H270008), the National Natural Science Foundation of China (grant no. 82204824), the Scientific Research Fund of Zhejiang Provincial Education Department (grant no. Y202351288), the Young Elite Scientists Sponsorship Program by China Association of Chinese Medicine (grant no. 2021-QNRC2-B13) and the Hangzhou Medical and Health Science and Technology Project (grant no. A20230054).

Availability of data and materials

Not applicable.

Authors' contributions

DS and LS conceptualized the study. DS, YX, YF and WC curated the data. DS, YX, QC, YZ and KG visualized the data. DS, YX, YF and WC wrote the original draft. LS, QC, YZ and KG wrote, reviewed and edited the manuscript. DS, KG and LS acquired funding. Data authentication is not applicable. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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September-2024
Volume 52 Issue 3

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Tumor type	Gene	Mutated samples	Samples tested	Rate of mutagenesis (%)
Gallbladder small cell carcinoma	SHH	1	17	5.88
	PTCH1	1	17	5.88
	PTCH2	1	17	5.88
	SMO	1	17	5.88
	GLI1	3	17	17.65
	GLI3	1	17	5.8
Central nervous system medulloblastoma (include all)	PTCH1	82	1,025	8.0
Central nervous system medulloblastoma (SHH subtype)	PTCH1	4	16	25.00
	SUFU	1	14	7.14
	SMO	1	15	6.67
Esophageal adenocarcinoma	PTCH1	32	580	5.52
	GLI3	190	468	40.60
	GLI2	56	468	11.97
Colon adenocarcinoma	PTCH1	119	1,657	7.18
	GLI3	113	943	11.98
	GLI2	75	926	8.10
Rectal adenocarcinoma	GLI3	43	470	9.15
Intestinal adenocarcinoma	PTCH1	9	84	10.71
	PTCH2	5	48	10.42
	SUFU	5	84	5.95
	GLI1	6	84	7.14
	GLI2	5	48	10.42
	GLI3	3	48	6.25
Gastric adenocarcinoma	GLI3	96	728	13.19
	GLI2	46	727	6.33
Pancreatic carcinoma	GLI3	336	1,682	19.98
	GLI2	128	1,652	7.75
Meningioma	PTCH1	24	352	6.82
	PTCH2	15	273	5.49
	SUFU	82	938	8.74
	SMO	153	1,583	9.67
Prostatic adenocarcinoma	GLI3	129	1,505	8.57
	GLI2	92	1,505	6.11
Malignant melanoma	PTCH1	190	2,526	7.52
	PTCH2	122	1,682	7.25
	GLI2	190	1,631	11.65
	GLI3	119	1,631	7.30
	GLI1	111	1,870	5.94
Basal cell carcinoma	PTCH1	491	933	52.63
	PTCH2	19	126	15.08
	SUFU	33	338	9.76
	SMO	154	578	26.64
	GLI3	31	126	24.60
	GLI2	23	126	18.25
	GLI1	15	142	10.56
Skin squamous cell carcinoma	SHH	9	69	13.04
	PTCH1	33	243	13.58
	PTCH2	14	69	20.29
	SUFU	8	150	5.33
	SMO	17	193	8.81
	GLI1	25	147	17.01
	GLI3	18	69	26.09
	GLI2	18	69	26.09

Oncology Reports

Hedgehog pathway and cancer: A new area (Review)

This article is mentioned in:

Abstract

Introduction

Figure 1.

Figure 2.

Genome instability mutations

Single-gene mutation

Mutation and tumor type

Table I.

Table I.

Multi-gene fusion

Non-mutational epigenetic reprogramming

HH and methylation

HH and histone modification

HH and non-coding (nc) RNA

Table II.

Table II.

Tumor-promoting inflammation

HH and Helicobacter pylori (Hp) infection

HH and chronic liver injury

HH and other tumor-promoting inflammation

HH and anti-inflammation

Avoiding immune destruction

HH and tumor-associated macrophages (TAMs)

HH and regulatory cells

HH and immune checkpoint inhibitors

Enabling replicative immortality and sustaining proliferative signaling

HH and human telomerase reverse transcriptase (hTERT)

HH and cell cycle regulation

Resisting cell death and evading growth suppressors

HH and TNF-related apoptosis-inducing ligand (TRAIL)

HH and the B-cell lymphoma-2 (Bcl-2) family

HH and the MYC family

HH and other cell death pathways

HH and radio resistance

Senescent cells

Activating invasion and metastasis

HH and hypoxia-induced epithelial-mesenchymal transition (EMT)

HH and the PI3K pathway in metastasis

HH and the MEK pathway in metastasis

HH and the Wnt/β-catenin pathway in metastasis

GLI1 and variants as key targets in metastasis

Inducing accessing vasculature

Dysregulating cellular metabolism

HH and glycolysis

HH and other metabolism

Drugs that regulate the HH pathway

HH inhibitors

Table III.

Table III.

Post-resistance treatment strategy

Natural drugs the regulate the HH pathway

Table IV.

Table IV.

Conclusions

Supplementary Material

Supporting Data

Acknowledgements

Funding

Availability of data and materials

Authors' contributions

Ethics approval and consent to participate

Patient consent for publication

Competing interests

References

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