*Contributed equally
Non-small cell lung cancer (NSCLC), a common type of cancer worldwide, is normally associated with a poor prognosis. It is difficult to treat successfully as it often metastasizes into brain or bone. Methods to facilitate the induction of effective programmed cell death (PCD) in NSCLC cells to reverse drug resistance, or to inhibit the invasion and migration of NSCLC cells, are currently under investigation. The present study summarized the regulatory functions of PCD, including apoptosis, autophagy and ferroptosis, in the context of NSCLC metastasis. It further summarized how regulatory agents, including long non-coding RNAs, circular RNAs and microRNAs, regulate PCD during the metastasis of NSCLC and characterized new potential diagnostic biomarkers of NSCLC metastasis.
Non-small cell lung cancer (NSCLC) is the primary histological type of lung cancer worldwide; it accounts for ~85% of all lung cancer cases and is a leading cause of cancer-related mortality. NSCLC is histologically divided into adenocarcinoma, squamous cell carcinoma and large cell carcinoma (
Tumor metastasis occurs as a complex cascade involving invasion, dissemination and distant colonization. Specifically, primary tumor cells invade the surrounding tissues, enter the circulatory system, survive during blood circulation, enter the parenchyma of distant tissues and finally colonize distant sites for subsequent proliferation (
Programmed cell death (PCD) refers to orderly and autonomous cell death that is controlled by a series of endogenous genes. PCD includes apoptosis, autophagy, pyroptosis, ferroptosis and necroptosis (
Aberrant apoptosis often leads to the progression and metastasis of various types of human cancer. Cell apoptosis inhibits metastasis at multiple stages ranging from invasion from the primary site to distant colonization (
Recently, a series of novel and important proteins have been reported to be associated with apoptosis, metastasis and prognosis of NSCLC by modulating epithelial-mesenchymal transition (EMT) progression or chemotherapeutic drug resistance, and by regulating various cancer-related signaling pathways in patients with NSCLC. The proteins identified in the regulation of NSCLC metastasis are summarized in
Several regulators inhibit NSCLC metastasis by inducing cell cycle arrest and apoptosis. Upregulation of thyroid hormone receptor interacting protein 13 (TRIP13) has been reported to be associated with tumor metastasis via EMT. TRIP13 knockdown can promote cell apoptosis by inducing cell cycle arrest at the S phase, and can inhibit the invasion and migration of NSCLC cells (
Some newly identified regulators have been reported to induce apoptosis and thus inhibit metastasis of NSCLC cells and this has been demonstrated to be associated with the clinical prognosis of patients with NSCLC. For example, homeobox (HOCX) 8 has been shown to be upregulated in NSCLC specimens and to function as a transcriptional activator that induces the expression of TGF-β1. High levels of HOXC8 have been reported to be associated with tumor-node metastasis and poor relapse-free survival in patients with NSCLC (
A number of lncRNAs have been reported to be involved in NSCLC metastasis by regulating apoptosis-related pathways (
Certain lncRNAs have been reported to act as suppressor genes in NSCLC metastasis by promoting apoptosis. LINC00632 was shown to be downregulated in NSCLC tissues, and low levels of LINC00632 can promote lymph node metastasis and distant metastasis. Furthermore, LINC00632 was revealed to inhibit tumor growth in nude mice with NSCLC by downregulating miR-1203(
LncRNAs have recently been identified as oncogenes that promote the invasion and migration of NSCLC cells. For example, the ncRNA plasmacytoma variant translocation 1 (PVT1) was shown to be highly expressed in 105 patients with NSCLC and to promote tumor-to-node metastasis. Knockdown of PVT1 was revealed to inhibit metastasis and proliferation by increasing LATS2 transcription via the Mdm2-p53 signaling pathway (
The lncRNA HNF1A-AS1 may promote cell invasion by targeting miR-17-5p in patients with NSCLC (
CircRNA is a new member of the ncRNA family that functions as a miRNA sponge to influence gene transcription. These RNAs are highly tissue-specific in mammals. An increasing number of circRNAs have been identified that regulate apoptosis in NSCLC metastasis. The specific and regulatory circRNAs involved in NSCLC metastasis that function by inducing or suppressing apoptosis in NSCLC cells have been summarized in the present study.
As presented in
Certain circRNAs serve as tumor suppressor gene. For instance, low hsa_circ_11780 expression levels have been reported to be associated with distant metastasis and poor overall survival. Overexpression of hsa_circ_11780 can significantly suppress the metastasis of NSCLC cells
Several circRNAs have been reported to be involved in chemotherapeutic drug resistance and the metastasis of NSCLC cells. Knockdown of circ_0001821 may inhibit metastasis and paclitaxel resistance in NSCLC cells via the miR-526b-5p/GRK5 pathway (
Furthermore, the expression of several circRNAs has been shown to be associated with clinicopathological parameters and prognostic value in patients with NSCLC. For example, CDR1as has been considered an independent prognostic factor for patients with NSCLC and knockdown of CDR1as can upregulate miR-7, a process that leads to the induction of cell apoptosis and G1/S arrest. Furthermore, high expression levels of CDR1as have been shown to be correlated with advanced TNM stage, increased lymph node metastasis and shorter overall survival time (
miRNAs are the most abundant endogenous small ncRNAs and are abnormally expressed in various types of human cancer. The miRNAs affecting NSCLC metastasis are summarized in
Furthermore, certain miRNAs have been reported to function as tumor suppressors to promote apoptosis in NSCLC cells. Tumor-suppressive miRNAs are significantly downregulated in NSCLC tissues and cell lines. Downregulation of a number of tumor-suppressive miRNAs has been reported to be correlated with the poor prognosis of patients with NSCLC, including miR-187-5p (
miR-718 has been demonstrated to serve a tumor suppressive role by suppressing NSCLC progression
Autophagy is critical in cancer development and metastasis, and serves a complex role in tumorigenesis in various types of cancer (
Previous research has suggested that autophagy induction inhibits EMT or metastasis in NSCLC cells (
The combination of apigenin and gefitinib has been shown to inhibit the activation of multiple oncogenes, including c-Myc, HIF-1α and phosphorylated EGFR, and this combination can also inhibit the AMPK signaling pathway in H1975 cells (
Consistently, previous studies have reported that the induction of autophagy enhances the sensitivity of NSCLC cells to chemotherapeutic drugs. For example, knockdown of NIPBL has been shown to enhance the chemosensitivity of NSCLC cells via the DNA damage response and autophagy pathways (
Notably, there is an opposing view that inducing autophagy increases chemoresistance or radioresistance in NSCLC cells. For example, troponin C1, slow skeletal and cardiac type can promote gemcitabine chemoresistance in NSCLC by inducing autophagy and this is negatively regulated by FOXO3(
Several studies have reported that autophagy induction promotes metastasis of NSCLC cells. miR-21 has been shown to be highly expressed in NSCLC tissues, and to be positively associated with lymphatic metastasis and clinical staging. This miRNA can promote the migration and invasion of A549 cells by regulating autophagy activity via the AMPK/ULK1 signaling pathway (
Ferroptosis is a newly reported iron-dependent PCD process that is characterized by the accumulation of an iron-dependent lethal lipid reactive oxygen species (ROS) response. To date, the induction of cell ferroptosis has provided a new insight into the design of anti-tumor drugs and is considered a promising strategy to inhibit tumor metastasis or overcome chemotherapeutic drug resistance (
Recently, studies examining the regulation of ferroptosis during cancer progression and metastasis have focused primarily on ncRNAs. Regulatory ncRNAs that regulate NSCLC progression and metastasis, including lncRNAs and circRNAs, have been gradually and widely reported (
Different types of PCD, such as apoptosis and autophagy, apoptosis and necroptosis, and necroptosis and ferroptosis, exist in close crosstalk (
The association between lncRNA, circRNA and miRNAs via miRNA recognition elements and negatively regulated the expression of miRNAs. The ceRNA regulatory network can be mRNA-miRNA-lncRNA, mRNA-miRNA-circRNA or mRNA-miRNA-lncRNA-circRNA. Each miRNA can have multiple target genes and multiple miRNAs can co-regulate the same gene. During the regulation of NSCLC metastasis, lncRNAs, circRNAs and miRNAs may interact with each other as ceRNAs, and can be involved in the progression and metastasis of NSCLC (
The rapid progress in RNA sequencing and analysis has revealed that a number of ncRNAs regulate tumor proliferation, invasion and migration of NSCLC cells. The present study summarized the regulatory role of PCD, including apoptosis, autophagy-related cell death and ferroptosis, in NSCLC metastasis. It also discussed the regulatory ncRNAs that promote PCD or inhibit the induction of PCD by acting as oncogenes or tumor suppressor genes.
In addition, necroptosis and pyroptosis have been newly identified as PCD mechanisms associated with various inflammatory or autoimmune diseases. The functions of necroptosis or pyroptosis in the context of cancer metastasis are complex; they possess both pro- and anti-tumor effects according to different pathological tissues, cell types or cancer stages during metastasis (
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XH was responsible for article selection and literature review. XH, LX, YL, WX and HZ wrote the manuscript. WX constructed figures. Data authentication is not applicable. All authors have read and approved the final manuscript.
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The authors declare that they have no competing interests.
Newly identified proteins that regulate the metastasis of NSCLC via promoting apoptosis. NSCLC, non-small cell lung cancer; TRIP13, thyroid hormone receptor interacting protein 13; HOX8, homeobox 8; USP39, ubiquitin-specific protease 39; PCGF3, polycomb group ring finger 3; ZEB1, zinc finger E-box binding homeobox 1; CNN3, Calponin 3; EVI5, ecotropic viral integration site 5; EIF5A2, eukaryotic translation initiation factor 5A2; CHAF1B, chromatin assembly factor 1 subunit B; FOXD1, forkhead box D1.
circRNAs regulate cell apoptosis and metastasis of NSCLC. The regulatory circRNAs on NSCLC metastasis are shown on a green background. The targeted miRNAs are shown on a pink background and their corresponding target genes are shown on a brown background; blue background indicates metastatic phenotype. circRNAs, circular RNAs; NSCLC, non-small cell lung cancer; miRNA, microRNA; FSCN1, fascin homolog 1, actin-bundling protein 1; AKT3, AKT serine/threonine kinase 3; NEAT, nuclear paraspeckle assembly transcript; EZH2, enhancer of zeste homolog 2(); KIF2A, kinesin family member 2A; TIPRL, TOR signaling pathway regulator-like.
lncRNAs regulate cell apoptosis and metastasis of NSCLC. The regulatory lncRNAs are shown on a red background. The targeted miRNAs are shown on a pink background and their corresponding target genes are shown on a brown background; blue background indicates phenotype; green background indicates circRNA. lncRNAs, long non-coding RNAs; NSCLC, non-small cell lung cancer; miRNA, microRNA; PVT1, plasmacytoma variant translocation1; SOX9, sex determining region Y-related high mobility group box9; MACC1, metastasis associated with colon cancer 1; DCLK1, doublecortin-like kinase 1; MALAT1, metastasis-associated lung adenocarcinoma transcript 1; COMMD8, copper metabolism MURR1 domain-containing 8; CRNDE, colorectal neoplasia differentially expressed; PSMA3AS1, PSMA3 antisense RNA 1; HMGA2, spindlin 1 high mobility group AT-hook 2; CASC7, cancer susceptibility candidate 7; CBR3AS1, CBR3 antisense RNA 1; Smad2, mothers against decapentaplegic homolog 2.
Regulatory miRNAs in human NSCLC. Several miRNAs serve a role as oncogenes to inhibit cell apoptosis and promote the metastasis of NSCLC, whereas others function as tumor suppressors to induce cell apoptosis and inhibit NSCLC metastasis. The regulatory miRNAs are shown on a pink background; corresponding target genes are shown on a brown background; green background indicates circRNA. miRNA, microRNA; NSCLC, non-small cell lung cancer; ATF2, transcription factor 2; ZEB1, zinc finger E-box binding homeobox 1; Runx3, runt-related transcription factor 3; MDM2, mouse/murine double minute 2; TEXs, tumor-derived exosomes; FGF2, fibroblast growth factor 2; CCND2, cyclin D2; CCNB1, cyclin B1.
Autophagy regulation in metastasis of NSCLC. The key targets involved in autophagy in metastasis of NSCLC are shown here. The role of autophagy is complex in tumorigenesis and metastasis of NSCLC. NSCLC, non-small cell lung cancer; Dvl2, dishevelled2; CDCA4, cell division cycle associated 4; CARM1, coactivator associated arginine methyltransferase 1; DRAM2, damage-regulated autophagy modulator 2; WIF1, Wnt inhibitory factor1; SAHA, suberoylanilide hydroxamic acid; NIPBL, nipped-B-like protein; TIPRL, TOR signaling pathway regulator-like; FOXO3, forkhead box 03.
Ferroptosis in tumorigenesis and metastasis of NSCLC. The key target genes and its corresponding miRNAs and lncRNAs are shown. NSCLC, non-small cell lung cancer; miRNA, microRNA; lncRNAs, long non-coding RNAs; EF24, diphenyldifluoroketone; SOX4, regulating SRY-box 4; ELAVL1, ELAV-like RNA-binding protein 1; xCT, System Xc (-); 27HC, 27-hydroxycholesterol.
Regulators of ferroptosis in NSCLC metastasis.
Protein or non-coding RNA | Target gene | Function in human cancer metastasis |
---|---|---|
Proteins | ||
EF24 | HMOX1 | EF24 exerted cytotoxicity against NSCLC via ROS accumulation ( |
xCT | / | xCT was highly expressed in a variety of tumors and associated with tumor metastasis. Erastin/sorafenib induced cisplatin-resistant NSCLC cell ferroptosis through inhibition of the Nrf2/xCT pathway ( |
NFS1 | / | NFS1 was highly expressed in lung adenocarcinoma. Inhibition of NFS1 induced ferroptosis |
GPX4 | / | Metastatic cells exhibited resistance to ferroptosis. High exposure to 27-hydroxycholesterol inhibited ferroptosis to increase metastatic capacity of tumor cells by inducing sustained expression of GPX4( |
lncRNAs | ||
lncOIP5-AS1 | miR-128/SLC1A11 | OIP5-AS1 was reported to induce metastatic phenotypes of NSCLC via miR-140-5p ( |
MIR503HG | miR-1273c/SOX4; SLC7A11 | Interference with the expression of MIR503HG inhibited NSCLC tumorigenesis and promoted cell apoptosis by regulating miR-489-3p and miR-625-5p ( |
MT1DP | miR-365a-3p/Nrf2 | MT1DP sensitized erastin-induced ferroptosis via regulating miR-365a-3p/Nrf2 axis in NSCLC cells ( |
H19 | miR-106b-5p/ACSL4 | Knockdown of H19 promoted tumor growth and suppressed ferroptosis by regulating the miR-106b-5p/ACSL4 pathway ( |
PVT1 | miR-214/p53; GPX4 | PVT1 regulated ferroptosis through miR-214-mediated TFR1 and TP53 expression ( |
ZFAS1 | miR-150-5p/SLC38A1 | Silencing of lncRNA ZFAS1 attenuated ferroptosis and pulmonary fibrosis progression by lncRNA ZFAS1 acting as a competing endogenous RNA and sponging miR-150-5p to downregulate SLC38A1 expression ( |
LINC00618 | SLC7A11 | LINC00618 induced ferroptosis by decreasing the expression of LSH and increasing the level of SLC7A11( |
LINC00336 | miR-6852/CBS | miR-6852 inhibited lung cancer cell growth by promoting ferroptosis and LINC00336 promoted tumorigenesis through LINC00336/miR-6852/CBS pathway ( |
circRNAs | ||
circ_008035 | miR-599/EIF4A1 axis | Circ_0008035 promoted gastric cancer progression and suppressed ferroptosis by upregulating EIF4A1 through sponging miR-599( |
circRNA c IARS | ALKBH5 | cIARS may be an important circRNA, positively regulating sorafenib-induced ferroptosis through suppressing the ALKBH5-mediated autophagy inhibition ( |
circ_0067934 | miR-545-3p/SLC7A11 | Circ_0067934 knockdown enhanced the levels of ferroptosis and induced thyroid cancer cell apoptosis by sponging and inhibiting miR-545-3p in thyroid cancer cells. Thus, circ_0067934 attenuated ferroptosis of thyroid cancer cells via the miR-545-3p/SLC7A11 pathway ( |
circ_0007142 | miR-874-3p/GDPD5 | Circ_0007142 was overexpressed in CRC. Inhibiting circ_0007142 promoted apoptosis and ferroptosis in CRC cells via the miR-874-3p/GDPD5 axis ( |
non-coding RNA | Target gene | Function in human cancer metastasis |
circIL4R | miR-541-3p/GPX4 | CircIL4R was abnormally overexpressed in HCC tissues and cells. CircIL4R functioned as an oncogene and inhibited ferroptosis in HCC via miR-541-3p/GPX4 pathway ( |
circTTBK2 | miR-761/ITGB8 | circTTBK2 knockdown, or overexpression of miR-761, suppressed invasion and promoted ferroptosis via targeting ITGB8 by sponging miR-761 in glioma ( |
circKIF4A | miR-1231/GPX4 | circKIF4A facilitated the malignant progress of papillary thyroid tumor by sponging miR-1231 and upregulating GPX4 expression ( |
circDTL | miR-1287-5p/GPX4 | CircDTL functioned as an oncogene and promoted NSCLC progression via the miR-1287-5p/GPX4 pathway ( |
circEPSTI1 | miR-375/409-3P/515-5p-SLC7A11 | CircEPSTI1 regulated ferroptosis in cervical cancer by sponging miR-375, miR-409-3p and miR-515-5p to upregulate SLC7A11 expression ( |
miRNAs | ||
miR-375 | SLC7A11 | miR-375 triggered ferroptosis via targeting SLC7A11 and attenuated the stemness of gastric cancer cells ( |
miR-4443 | FSP1/METLL3 | miR-4443 promoted cisplatin resistance in NSCLC cells by regulating FSP1 in an m6A manner via METLL3, a direct target gene of miR-4443( |
miR-324-3p | GPX | miR-324-3p enhanced ferroptosis in cisplatin-resistant A549 cells via miR-324-3p/GPX4 in NSCLC cells ( |
NSCLC, non-small cell lung cancer; ROS, reactive oxygen species; lncRNA, long non-coding RNA; miRNA/miR, microRNA; circRNA, circular RNAs; CRC, colorectal cancer; HCC, hepatocellular carcinoma.