Autophagy regulation by microRNAs in chemotherapy resistance (Review)

  • Authors:
    • Tianqiao Huang
    • Zhen Xu
    • Lin Cao
    • Yuanyuan Lian
    • Yichuan Huang
  • View Affiliations

  • Published online on: June 22, 2020     https://doi.org/10.3892/or.2020.7655
  • Pages: 791-797
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Abstract

Chemotherapy, as an adjuvant therapy, utilizes drugs to treat cancer, and resistance to therapeutic drugs limits the efficacy of chemotherapy treatments. Several mechanisms have been proposed to improve the effect of tumor chemotherapy in order to overcome drug resistance. Among these, autophagy mediated by microRNAs (miRNAs) is one of the primary mechanisms. A large number of molecules targeted by miRNAs are involved in each step of the autophagic pathway. Recent advancement in chemotherapy research has revealed that miRNAs involved in the autophagy process target some of these molecules, thereby influencing the therapeutic effect of chemotherapy drugs. Thus, miRNAs appear to be potential tools or targets with which to suppress tumor growth and should be studied in further details for their clinical application against drug resistance.

Introduction

Chemotherapy, as the first-line of treatment or adjuvant treatment for tumors, often delivers mixed outcomes (1). The primary reason for this is drug resistance encountered during chemotherapy. Overcoming drug resistance by tumors is a basic and challenging initiative to resolve the insensitivity of tumors toward chemotherapy. Recent studies have focused on microRNAs (miRNAs) as a tool to suppress tumorigenesis, which is expected to assist in the development of effective chemotherapy drugs (2).

miRNAs are endogenous non-coding RNAs with an approximate length of 23 nucleotides, which can regulate the expression of target genes via interaction with its 3′-untranslated regions (3). miRNAs are involved in diverse biological and pathological processes, including the generation and development of cancer. They also act on target genes to inhibit tumor resistance to chemotherapy drugs (4). Various known mechanisms of miRNA regulation include the overexpression of multidrug resistance (MDR) transporters, defects in cell-cycle and the apoptotic machinery, induction of autophagy, alternation of anticancer drug metabolism, alteration in drug targets, DNA repair, and disruption of redox homeostasis. Among these, autophagy regulation is one of the most critical mechanisms (5) that demonstrates an important mechanism to overcome chemotherapy resistance of various tumors (6).

In 2016, Yoshinori Ohsumi won the Nobel Prize in physiology or medicine in recognition of his outstanding achievements in emphasizing the importance of autophagy as the key player in understanding human diseases. Autophagy is the quality-control mechanism of a cell to regulate its cellular homeostasis (7). It plays a dual role in tumorigenesis, either as a promoter or suppressor of tumors (8). Recent studies, however, have focused on the protective effect of autophagy on tumor cells and have further strengthened the belief that autophagy can promote apoptosis of tumor cells and inhibit their proliferation (6). A large number of molecules are involved in each step of the autophagic pathway (6,911) (Fig. 1), and, during this process, miRNAs target some of these molecules and thereby participate in the generation of tumor chemotherapy resistance.

The present review summarizes some of the relevant works in recent years and their perspective on the role of miRNA-mediated autophagy in tumor chemotherapy resistance.

miRNA-mediated autophagy changes with respect to drug resistance in tumor treatment

miRNA-mediated autophagy initiation changes the pattern of drug resistance in tumors

Autophagy initiation involves 2 major complexes: The UNC-51–like autophagy-activating kinase (ULK)1 complex and the class III PI 3-kinase (PI3K) complex (12). Some miRNAs target any one or more of the above-mentioned 2 compounds or their inhibitors and trigger autophagy alteration, thereby changing the tumor drug resistance pattern (Table I).

Table I.

miRNA-targets related to autophagy initiation.

Table I.

miRNA-targets related to autophagy initiation.

A, ULK1 complex

miRNAsmiRNA expressionTargetsTarget expressionAutophagy levelCancerChemotherapy resistance
miR-26a/bUpULK1DownDownHCCDown
miR-106aUpULK1DownDownLung adenocarcinomaDown
miR-25DownULK1UpUpBreast cancerUp
miR-409-3pUpFip200DownDownOvarian cancerDown

B, PI3K complex

miRNAsmiRNA expressionTargetsTarget expression AutophagylevelCancerChemotherapy resistance

miR-140-5pUpATG14DownDownMyelomaDown
miR-152UpATG14DownDownOvarian cancerDown
miR-30aUpBeclin-1DownDownOsteosarcomaDown
miR-30dDownBeclin-1UpUpUTCUp
miR-216bUpBeclin-1, UVRAG and ATG5DownDownMelanomaDown
miR-409-3pUpBeclin-1DownDownColon cancerDown
miR-216bUpBeclin-1DownDownNSCLCDown

C, mTOR and mTOR pathway

miRNAsmiRNA expressionTargetsTargets expressionAutophagy levelCancerChemotherapy resistance

miR-338-3pUpmTORDownUpColon cancerUp
miR-193-5pUpmTORDownUpGliomaUp
miR-155UpPTENDownDownOsteosarcomaDown
miR-21DownPTENUpUpBreast cancerUp
miR-21UpPTENDownDownHCCDown
miR-142-3pUpHMGB1DownUpNSCLCUp
miR-410-3pUpHMGB1DownUpPDACUp
miR-218UpHMGB1DownUpEndometrial cancerUp
miR-22UpHMGB1DownUpOsteosarcomaUp
miR-34aUpHMGB1DownUpRetinoblastomaUp

[i] Up, upregulated; Down, downregulated; HCC, hepatocellular carcinoma; UTC, undifferentiated thyroid carcinoma; NSCLC, non-small cell lung cancer; PDAC, pancreatic ductal adenocarcinoma; ULK1, UNC-51-like autophagy-activating kinase 1; FIP20, focal adhesion kinase family interacting protein of 200 kDa; ATG, autophagy-related gene; UVRAG, UV resistance-associated gene; PTEN, phosphatase and tension homolog; HMGB1, high-mobility group box 1.

The ULK1 complex includes ULK1, autophagy-related gene (ATG)13 protein, focal adhesion kinase family interacting protein of 200 kDa (FIP200) and ATG101 in humans. ULK1 is a part of a family of ULK1-4 kinases that play an important role in autophagy (12). ULK1 is targeted by miRNA-26a/b, and the in vitro overexpression of ULK1 promotes apoptosis by inhibiting autophagy; moreover, the overexpression of miRNA-26a/b has been shown to enhance the sensitivity of hepatocellular carcinoma cells (HCC) to doxorubicin in vivo in xenograft models of nude mice (13). In another report, ULK1-mediated autophagy protected lung adenocarcinoma cells from the toxic effects of tyrosine kinase inhibitors (TKIs), and high expression of miR-106a was found to inhibit ULK1 expression, reduce autophagy, and increase the cytotoxic effects of TKIs (14). Another study showed that isoliquiritugenin (ISL), a natural flavonoid, possesses anticancer properties and that it could inhibit the expression of miR-25, leading to the upregulation of its target gene ULK1 and an increase in the extent of autophagy. These events ultimately led to the accelerated degradation of ATP-binding cassette sub-family G member 2 (ABCG2) through the autophagy-lysosomal pathway, resulting in improved toxicity of chemotherapy drugs against breast cancer cells (15). FIP200, a large ULK1-interacting protein, has a predicted coiled-coil protein involved in scaffolding (16). Cheng et al reported that the expression of miR-409-3p was enhanced in cisplatin-sensitive cells when compared with cisplatin-resistant cells, and the overexpression of miR-409-3p decreased the expression of FIP200 and the related autophagy, thereby increasing the cisplatin sensitivity of ovarian cancer cells (17).

The PI3K complex occurs downstream of ULK1. The PI3K complex consists of autophagy and Beclin-1 regulator 1 (AMBRA1), Beclin-1, vacuolar protein sorting 34 (VPS34) (phosphatidylinositol), VPS15, UV resistance-associated gene (UVRAG) and ATG14L. ATG14L is a Beclin-1-associated autophagy key regulator (18). lncRNAs are non-coding RNA with a length of more than 200 nucleotides. lncRNA lacks the coding ability, but it is a functional molecule (19) with multiple effects on miRNAs (20). An lncRNA can be used as an miRNA sponge as it competes with miRNA to bind to the target mRNA, and some lncRNAs can also be converted into miRNAs. It was found that knockdown of Lnc0515 induced the overexpression of miR-140-5p, which targets ATG14, one of the components of the PI3K complex. This event eventually caused inhibition of autophagy, thereby alleviating the chemoresistance of myeloma cells (18). ATG14 is also known to be targeted by miR-152, while the transcription factor early growth response 1 (EGR1) regulates miR-152 upstream, the overexpression of either EGR1 or miR-152 led to the inhibition of ATG14 expression as well as the inhibition of autophagy, eventually increasing the cisplatin toxicity to ovarian cancer cells and thereby weakening drug resistance (21). Luciferase reporter assay identified that several miRNAs, such as miR-30a, which directly binds to the 3′-UTR of Beclin-1, inhibited Beclin-1 expression. When miR-30a was overexpressed, Beclin-1-mediated autophagy was inhibited, which not only promoted the chemotherapy-induced apoptosis of osteosarcoma cells but also enhanced the toxicity of sorafenib to renal cell carcinoma (RCC) cells (22,23). The sensitivity of undifferentiated thyroid carcinoma (UTC) to cisplatin is heterogeneous, which may be related to the downregulation of miR-30d; both in vivo and in vitro experiments confirmed that the downregulation of miR-30d could target and promote Beclin-1 expression, leading to an increase in autophagy and in the insensitivity of UTC cells to cisplatin (24). miR-216b was found to target Beclin-1, UVRAG, and ATG5, 3 essential autophagy genes, directly to weaken autophagy and enhance the antitumor activity of the drug vemurafenib in BRAF (V600E) melanoma cells (25). In addition, Tan et al reported that the overexpression of miR-409-3p inhibited Beclin-1 expression and autophagy, and thus enhanced the chemosensitivity of colon cancer cells to the drug oxaliplatin in vivo and in vitro (26). Other research also noted a reduction in the expression level of miR-216b in paclitaxel-treated non-small cell lung carcinoma (NSCLC) cells. As the expression level of miR-216b increased, the Beclin-1 mRNA translation level decreased, autophagy was inhibited, and the toxicity of paclitaxel to NSCLC was enhanced (27). High-mobility group box 1 (HMGB1) is a type of non-histone protein that has been widely reported to play a key role in the induction of autophagy. Several studies have suggested that HMGB1 binds to the PI3K complex to facilitate autophagic progression (2833). miR-142-3p was found to directly downregulate HMGB1, inhibit autophagy induced by anticancer drugs, and increase the chemosensitivity of NSCLC in both in vitro and in vivo experiments (29). In vivo and in vitro experiments showed that the expression of miR-410-3p was downregulated in tumor cells and in transplanted tumor tissues with chemotherapy-resistance to gemcitabine; after intervention, high expression of miR-410-3p was targeted to inhibit HMGB1 and its induced autophagy, which resulted in enhanced sensitivity of chemotherapy (30). HMGB1 is also the target gene of miR-218, which binds to the 3′-UTR of this gene, inhibits the expression of the target gene, inhibits autophagy, and was found to improve the sensitivity of endometrial cancer cells to paclitaxel chemotherapy (31). Similarly, miR-22 and miR-34a were also found to target HMGB1 and inhibit its expression, inhibit autophagy, and restore the sensitivity of osteosarcoma and retinoblastoma cancer cells to chemotherapy drugs (32,33).

mTOR, a serine/threonine kinase, is a master regulator of cellular metabolism and the key regulator of autophagy. It forms 2 complexes: mTORC1 and mTORC2; the former inhibits autophagy-initiation by preventing the formation of ULK1 and PI3K complexes (34). miR-338-3p was found to increase autophagy by downregulating the expression of its target mTOR, leading to the resistance of colon cancer cells containing P53 mutants to 5-fluorouracil (35). Downregulation of lncRNA-CASC2 in glioma resulted in an increase in the miR-193a-5p expression level and a decrease in the mTOR expression, which further induced protective autophagy, resulting in temozolomide resistance (36). The PI3K/PTEN/Akt/mTOR signaling pathway has been implicated in the resistance to chemoradiotherapy (37). Phosphatase and tension homolog (PTEN), which encodes a phosphatase protein, is an essential tumor-suppressor gene. It activates the mTOR pathway and inhibits autophagy (38). In MG-63/ADM osteosarcoma cells, miR-155, p-AKT, and p-mTOR were found to be overexpressed. PTEN, the target gene of miR-155, is a positive regulator of autophagy, and the overexpression of miR-155 was found to inhibit PTEN and reduce autophagy induction, simultaneously. In addition, expression of AKT and mTOR was found to activate the PI3K/AKT/mTOR signaling pathway and inhibit autophagy, which in turn led to increased adriamycin resistance in tumor cells (39). The knockdown of miR-21 expression in breast cancer cells was found to lead to an increase in the expression of PTEN and the inhibition of the activation of AKT. This event blocked the PI3K/AKT/mTOR signaling pathway, increased autophagic cell death, and partially overcame the endocrine resistance of tumor cells to tamoxifen and fulvestrant (40). Another study reported that miR-21 expression was higher in HCC cells resistant to sorafenib, which resulted in decreased expression of PTEN, increased activation of the AKT/mTOR pathway, and significant inhibition of autophagy (41).

miRNA-mediated autophagosome formation changes the pattern of drug resistance in tumors

The two essential complexes of autophagosomes are ATG12-ATG5-ATG16L and LC3B (42,43). Other miRNAs target any one or more of the above-mentioned two compounds, trigger autophagy alteration, and change the response of the tumor to chemotherapy drugs (Table II). ATG5-ATG12 conjugation depends on ATG7 (an E1-like ubiquitin-activating enzyme) and ATG10 (an E2-like ubiquitin carrier protein), which pairs with ATG16L dimers to form the ATG5-ATG12-ATG16L complex; this complex associates with the outer membrane of the extending phagophore (10). By competitively inhibiting miR-23b-3p, lncRNA MALAT1 was found to increase the expression of ATG12, which in turn led to increased autophagy and drug resistance in gastric cancer cells (44). miR-410 was found to reduce expression of ATG16L1 by directly targeting its 3′-UTR, subsequently inhibiting autophagy and improving the response of osteosarcoma cells to chemotherapy drugs (rapamycin, adriamycin, and cisplatin) (45). ATG5 is an miR-181a target, and overexpression of miR-181a was found to inhibit ATG5 and increase the sensitivity of gastric cells SGC7901/CDDP to cisplatin in a mouse model, in which tumor xenografts were downsized (46). PU.1-miR-142-3p targets ATG5/ATG16L1. Upregulation of heterotopic miR-142-3p, was found to reduce sorafenib-induced autophagy, enhance sorafenib-induced apoptosis, and inhibit cell growth, enhancing HCC cell sensitivity to sorafenib (47). ATG12 and HMGB2, target genes of miR-23b-3p, are essential elements of autophagy. Following miR-23b-3p overexpression, the expression and ATG12 and HMGB2-mediated autophagy are inhibited, and as a result, the sensitivity of gastric cancer cells to chemotherapy drugs is increased (48).

Table II.

miRNA-targets related to autophagosome formation.

Table II.

miRNA-targets related to autophagosome formation.

A, ATG12-ATG5-ATG16L complex

miRNAsmiRNA expressionTargetsTarget expressionAutophagy levelCancerChemotherapy resistance
miR-23b-3pDownATG12UpUpGastric cancerUp
miR-410UpATG16LDownDownOsteosarcomaDown
miR-181aUpATG5DownDownGastric cancerDown
miR-142-3pUpATG5/ATG16LDownDownHCCDown
miR-23b-3pUpATG12DownDownGastric cancerDown

B, LC3B complex

miRNAsmiRNA expressionTargetsTarget expressionAutophagy levelCancerChemotherapy resistance

miR-34aUpATG4BDownDownProstate cancerDown
miR-34c-5pUpATG4BDownDownCervical cancerDown
miR-375UpATG7DownDownBreast cancerDown
miR-520bUpATG7DownDownHCCDown
miR-17UpATG7DownDownNSCLCDown
miR-423-5pUpATG7DownDownHCCDown
miR-17DownATG7UpUpGlioblastomaUp
miR-119a-5pUpATG7DownDownHCCDown

[i] Up, upregulated; Down, downregulated; HCC, hepatocellular carcinoma; NSCLC, non-small cell lung cancer; ATG, autophagy-related gene; LC3B, microtubule-associated protein light chain 3.

Microtubule-associated protein light chain 3 (LC3B) is another ubiquitin-like system involved in autophagosome formation. LC3B is encoded by ATG8 and it is a product of the cleavage of ProLC3 by ATG4 and ATG7. One previous study showed that hypermethylation causes downregulation of miR-34a, which results in the upregulation of miR-34. Demethylated miR-34a targets ATG4B, thereby downregulating ATG4B-induced autophagy by activating the AMPK/mTOR pathway, with an increased sensitivity to chemotherapy in prostate cancer (PCa) cells (49). THP (pirarubicin) treatment significantly reduced the size of the transplanted tumor. In vivo experiments revealed that the overexpression of miR-34c-5p in cells led to a decrease in the inhibition of autophagy by ATG4B, which increased the sensitivity to THP (50). Several studies have shown that multiple miRNAs target ATG7 to mediate autophagy in order to alter the pattern of drug resistance in tumors. For example, MTT assay demonstrated that dual treatment of inhibitors of abelson non-receptor tyrosine kinase (c-ABL) (imatinib) and EGFR (lapatinib) suppressed breast cancer cell growth and upregulated miRNA-375; the overexpression of miR-375 decreased the expression of its target ATG7, which in turn mediated autophagy, which is beneficial in preventing fulvestrant resistance (5156). Apigenin was found to significantly increase adriamycin sensitivity, induce the overexpression of miR-520b, and inhibit ATG7-related autophagy in BEL-7402/ADM cells; these results were verified in a nude mouse xenograft as well as in vitro (52). The expression level of lncRNA-XIST (an oncogene in colorectal cancer) was found to be significantly increased in cisplatin-resistant A549 cells. Hence, lncRNA-turbulence/miR-17/autophagy may be a target for improving chemotherapy resistance in NSCLC patients by the knockdown of lncRNA-XIST to regulate miR-7 expression and inhibit ATG7 expression so as to restore the sensitivity of cisplatin-resistant A549 cells (53). miR-423-5p is inactivated by ceramide. A previous study reported that miR-423-5p downregulates the expression of its target ATG7, leading to autophagy inhibition. In addition, miR-423-5p was found to downregulate the expression of ERK to inhibit the proliferation of cells. Altogether, these results in a previous study implied that miR-423-5p induced the inhibition of autophagy and cell proliferation increased the apoptosis of cells and improved the sensitivity of HCC cells to sorafenib (54). miR-17 was demonstrated to negatively regulate ATG7, and the downregulation of miR-17 was found to increase the expression of ATG7. miR-17 also enhanced autophagy, drug sensitivity of temozolomide, and the sensitivity of glioblastoma to low-dose ionizing radiation (55). Moreover, miR-199a-5p was found to specifically inhibit the expression of ATG7, reduce autophagy, and enhance the inhibitory effect of cisplatin in regards to the proliferation of HCC cells (56).

miRNA-mediated autolysosome maturation changes the pattern of drug resistance in tumors

The development from autophagosome to autolysosome involves a complex system of new lysosomes and several large molecules that affect this process by altering the lysosomal activity. Lysosome-associated protein transmembrane 4 β (LAPTM4B) is one such molecule whose knockdown not only increases the lysosomal pH and inhibits lysosome and autophagosome fusion (57) but also causes lysosomal membrane permeabilization (58). LAPTM4B was reported as the target of miR-489 and was downregulated by miR-489. Overexpression of miR-489 was found to induce LAPTM4B-related autophagy and inhibit drug resistance in breast cancer cells (59). LAMP-1 and LAMP-2 are proteins that play a vital role in lysosomal biogenesis (60). miR-487-5p targets LAMP2, and knockdown of miR-487-5p was found to markedly increase levels of LAMP-2, enhance autophagy, and decrease cellular proliferation, whereas, miR-487b-5p suppression promoted temozolomide (TMZ) resistance in lung cancer cells (61).

Conclusion and future directions

The regulation of autophagy by non-coding miRNAs has been extensively researched in the last couple of years. Although a change in chemotherapy resistance for a single tumor may need the involvement of several different types of miRNAs, a single miRNA is capable of imparting chemotherapy resistance in a wide variety of tumors. Thus, resistance to a tumor chemotherapy drug can develop through various regulatory mechanisms of miRNAs via different target genes at every stage of autophagy. However, there are limitations to the studies on miRNAs and the involvement of autophagy in drug resistance. On one hand, some studies have focused on the relationship between an miRNA and its target genes related to autophagy at the molecular level through in vitro experiments. In addition, other studies have performed both in vitro experiments as well as animal models. In some studies, the experimental verification was confined to tumor transplantation, but not to human tissues. On the other hand, when multiple miRNAs are involved in the autophagy process of tumorigenesis, it is important to explore the specificity of the miRNA(s) or the specific steps(s) involved by using a large group of studies. miRNAs are thus regulated by lncRNAs or other upstream factors, making the regulation process extremely complex, which necessitates further research on the elaborate mechanisms involved in this process. Further insight into the exciting and complex mechanisms of miRNA-regulated autophagy is expected to be valuable in a variety of therapeutic applications, including the chemotherapy resistance of various types of tumors.

Acknowledgements

We thank all the individuals who assisted in this research.

Funding

No funding was received.

Availability of data and materials

All information included in this Review was supported by relevant references.

Authors' contributions

YH reviewed and edited the manuscript. TH prepared the original draft and completed the manuscript. ZX and LC designed the figures and YL completed the document retrieval. 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-2020
Volume 44 Issue 3

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Online ISSN:1791-2431

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Spandidos Publications style
Huang T, Xu Z, Cao L, Lian Y and Huang Y: Autophagy regulation by microRNAs in chemotherapy resistance (Review). Oncol Rep 44: 791-797, 2020
APA
Huang, T., Xu, Z., Cao, L., Lian, Y., & Huang, Y. (2020). Autophagy regulation by microRNAs in chemotherapy resistance (Review). Oncology Reports, 44, 791-797. https://doi.org/10.3892/or.2020.7655
MLA
Huang, T., Xu, Z., Cao, L., Lian, Y., Huang, Y."Autophagy regulation by microRNAs in chemotherapy resistance (Review)". Oncology Reports 44.3 (2020): 791-797.
Chicago
Huang, T., Xu, Z., Cao, L., Lian, Y., Huang, Y."Autophagy regulation by microRNAs in chemotherapy resistance (Review)". Oncology Reports 44, no. 3 (2020): 791-797. https://doi.org/10.3892/or.2020.7655