Elsevier

Pharmacological Research

Volume 161, November 2020, 105133
Pharmacological Research

Review
Autophagy-related microRNAs: Possible regulatory roles and therapeutic potential in and gastrointestinal cancers

https://doi.org/10.1016/j.phrs.2020.105133Get rights and content

Abstract

Gastrointestinal (GI) cancers with a high incidence rate and adverse complications are associated with severe morbidity and mortality around the world. It is well recognized that early detection of the disease results in longer survival rate and better quality of life. Autophagy, an intracellular regulatory process, has been shown to play an essential role in the pathogenesis of various malignancies including GI cancers. MicroRNAs (miRNAs) are small non-coding RNAs that have regulatory functions in tumor cells and possess potential diagnostic values in early detection of cancers. It has been recently demonstrated that these molecules have modulatory effects on multiple steps of autophagy process occurring in GI malignancies. In this review, we aimed to highlight the role of autophagy-related microRNAs on GI cancer as potential targets for cancer therapy.

Introduction

Gastrointestinal (GI) cancers as one of the most frequent human malignancies [1] account for nearly 15 % of cancer-related mortalities around the world [2]. Gastric and esophageal cancers are the fourth and sixth most common cancers worldwide. The frequency of pancreatic cancer is low but is the fifth most prevalent cause of cancer-related mortalities. Liver and gallbladder cancers are quite uncommon but carry a poor prognosis [3]. Although surgery is considered as the primary curative treatment for most of GI malignancies, some of these tumors are unrespectable at the time of diagnosis and the 5-year survival rate for patients undergoing resection alone remains poor. The combination of surgical resection and radiation therapy as well as adjuvant or neoadjuvant chemotherapy modestly ameliorate long-term survival [4,5]. Currently, serum tumor markers, immunoassay, endoscopy, histopathology of pepsinogen, Helicobacter pylori (H. pylori) antibodies and carcinoembryonic antigen (CEA) are applied for disease evaluation and diagnosis but are not useful for early detection [6]. MicroRNAs (miRNAs), which are highly conserved small non-coding RNAs, modulate numerous biological processes including carcinogenesis [7]. Their dysregulated expression has been well-investigated and they are shown to be hopeful diagnostic biomarkers for a plethora of human malignancies such as GI cancers [8]. Autophagy, cellular self-digestion machinery, provides the cell with sufficient energy through intracellular material degradation under stressful stimuli. It serves as a self-defensive mechanism that promotes the tumor cell survival by preventing toxic waste accumulation [9]. However, autophagic dysfunction leads to improper organelle and protein degradation which are essential for maintaining tumor cell survival and ultimately results in autophagic cell death [10]. Mounting data shows the critical role of autophagy in numerous pathophysiological states including inflammation [11], vascular [12]and neurodegenerative disorders [13], as well as cancers [14].

There is an accumulative body of evidence on autophagy regulation by miRNAs. Study on this interaction tries to find out the precise signaling cascade and the exact involved components which could be targets for cancer diagnosis, prognosis and treatment. The aim of this review is to summarize current findings on the significant modulatory roles of miRNAs on autophagy process in GI cancers (Table 1).

Section snippets

MicroRNAs: biogenesis and regulatory roles in cancer

Genomes in organisms encode for diverse non-coding RNAs such as miRNAs, circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snRNAs). Among these, miRNAs are small (18–22 nucleotide sequence) non-coding RNAs found in intronic regions of protein-coding genes or within intergenic regions of genomes [[15], [16], [17], [18]]. The biogenesis of miRNAs is a stepwise cellular process (Fig. 1). MiRNA genes are transcribed into primary micro

Autophagy and cancer

In autophagy, intracellular components are captured in autophagosomes and delivered to lysosomes to be recycled and degraded [37]. This process has dual pro- and anti-tumorigenic properties. Autophagy can promote the suppression of tumors during cancer initiation while it can promote tumors during progression [38]. Both oncogenes and tumor suppressor genes are implicated in regulation of autophagy, so linking autophagy directly to cancer progression and development. Furthermore, autophagy

MicroRNAs regulate autophagy in gastrointestinal cancers

Stress signals such as growth factor deprivation, energy crisis or starvation mediate the up- or downregulation of miRNAs and subsequent activation of stress responses such as autophagy [52]. Recently, mounting data has reported that miRNAs and long non-coding RNAs (lncRNAs) can modulate in vivo andin vitro regulation of autophagy by targeting gene expression at chromatin organization level, co- or post transcriptionally [53].

MiR-30d inhibits beclin1, leading to sensitization of anaplastic

Regulation of autophagy/miRNAs by natural products in GI cancer

Natural products are usually small molecules such as urea as well as complex structures such as Taxol. Recent studies determined the biological activity and chemical structures of many natural products. The cancer-protective capabilities of natural products were investigated in many studies [[241], [242], [243]]. Resveratrol is a polyphenol found largely in the skin of raspberries, grapes, mulberries, and blueberries, and considered to have antioxidative benefits. Tili et al. found that

Nanocarrier delivery system

Nanocarriers have been developed for encapsulation of various drugs and efficient delivery; in this way, they can improve the efficacy of the treatment. There are many nanocarriers designed for delivery of various agents such as drugs and genes. PLGA particles showed good biodegradability and biocompatibility, which can be useful in the miRNA delivery [248]. Liang et al. used PLGA/PEI nanoparticles for delivery of miRNA in HePG2 cells (human hepatocellular carcinoma cells). They found that

Conclusion

According to the current review, autophagy has been suggested to serve as a tumor suppressor process in the early phases but it might promote tumor growth, spread, and treatment resistance in later phases of cancer. Thus, autophagy is considered as a stage-dependent player in cancer progression. Furthermore, the implication of miRNAs as diagnostic and prognostic biomarkers in multiple cancers has recently been reviewed. Importantly, it has been indicated that miRNAs have modulatory roles on the

Funding

None.

Author contributions

HM and AS contributed to the conception, design, statistical analysis and drafting of the manuscript. MH-P, and MN contributed to data collection and manuscript drafting. All authors approved the final version for submission.

Ethics approval and consent to participate

This study was considered exempt by the KAUMS Institutional Review Board.

Consent for publication

Not applicable.

Declaration of Competing Interest

Authors declare that there is no conflict of interest.

Acknowledgements

Not applicable.

References (251)

  • H. Ji et al.

    miR-124 regulates EMT based on ZEB2 target to inhibit invasion and metastasis in triple-negative breast cancer

    Pathol. Res. Pract.

    (2019)
  • J. Wang et al.

    MicroRNA-135a promotes proliferation, migration, invasion and induces chemoresistance of endometrial cancer cells

    European journal of obstetrics & gynecology and reproductive biology: X

    (2020)
  • N. Mizushima

    The role of the Atg1/ULK1 complex in autophagy regulation

    Curr. Opin. Cell Biol.

    (2010)
  • S.K. Bhutia et al.

    Autophagy: cancer’s friend or foe?

    Adv. Cancer Res.

    (2013)
  • S. Wang et al.

    Sotetsuflavone suppresses invasion and metastasis in non-small-cell lung cancer A549 cells by reversing EMT via the TNF-alpha/NF-kappaB and PI3K/AKT signaling pathway

    Cell Death Discov.

    (2018)
  • Y. Zhang et al.

    Regulation of autophagy by miR-30d impacts sensitivity of anaplastic thyroid carcinoma to cisplatin

    Biochem. Pharmacol.

    (2014)
  • H. Zhou et al.

    Autophagy regulation and its role in gastric cancer and colorectal cancer

    Cancer Biomark.

    (2016)
  • X. Zhang et al.

    Novel role of miR-133a-3p in repressing gastric cancer growth and metastasis via blocking autophagy-mediated glutaminolysis

    J. Exp. Clin. Cancer Res.

    (2018)
  • Z. Xu et al.

    MIR-1265 regulates cellular proliferation and apoptosis by targeting calcium binding protein 39 in gastric cancer and, thereby, impairing oncogenic autophagy

    Cancer Lett.

    (2019)
  • J. Zhao et al.

    MiR-181a suppresses autophagy and sensitizes gastric cancer cells to cisplatin

    Gene

    (2016)
  • X. Zhang et al.

    Circular RNA circNRIP1 acts as a microRNA-149-5p sponge to promote gastric cancer progression via the AKT1/mTOR pathway

    Mol. Cancer

    (2019)
  • L. Xin et al.

    METase promotes cell autophagy via promoting SNHG5 and suppressing miR-20a in gastric cancer

    Int. J. Biol. Macromol.

    (2019)
  • X. Zhang et al.

    Novel role of miR-133a-3p in repressing gastric cancer growth and metastasis via blocking autophagy-mediated glutaminolysis

    J. Exp. Clin. Cancer Res.

    (2018)
  • B. Li et al.

    MicroRNA-148a-3p enhances cisplatin cytotoxicity in gastric cancer through mitochondrial fission induction and cyto-protective autophagy suppression

    Cancer Lett.

    (2017)
  • P. Kong et al.

    The microRNA-423-3p-Bim axis promotes cancer progression and activates oncogenic autophagy in gastric cancer

    Mol. Ther.

    (2017)
  • F. Du et al.

    MicroRNA-143 enhances chemosensitivity of Quercetin through autophagy inhibition via target GABARAPL1 in gastric cancer cells

    Biomed. Pharmacother.

    (2015)
  • A. Jemal et al.

    Cancer statistics, 2009

    CA Cancer J. Clin.

    (2009)
  • F. Bray et al.

    Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

    CA Cancer J. Clin.

    (2018)
  • Y. Luo et al.

    Clinical outcomes after surgical resection of colorectal cancer in 1,294 patients

    Hepatogastroenterology

    (2012)
  • Pottgen C, Stuschke M

    Radiotherapy versus surgery within multimodality protocols for esophageal cancer--a meta-analysis of the randomized trials

    Cancer Treat. Rev.

    (2012)
  • H. Schwarzenbach et al.

    Clinical relevance of circulating cell-free microRNAs in cancer

    Nat. Rev. Clin. Oncol.

    (2014)
  • R.T. Netea-Maier et al.

    Modulation of inflammation by autophagy: consequences for human disease

    Autophagy

    (2016)
  • G.R. De Meyer et al.

    Autophagy in vascular disease

    Circ. Res.

    (2015)
  • F.M. Menzies et al.

    Compromised autophagy and neurodegenerative diseases

    Nat. Rev. Neurosci.

    (2015)
  • X. Jiang et al.

    Autophagy in cellular metabolism and cancer

    J. Clin. Invest.

    (2015)
  • M. Esteller

    Non-coding RNAs in human disease

    Nat. Rev. Genet.

    (2011)
  • J.S. Nahand et al.

    microRNAs: new prognostic, diagnostic, and therapeutic biomarkers in cervical cancer

    J. Cell. Physiol.

    (2019)
  • P. Khani et al.

    Genetic and epigenetic contribution to astrocytic gliomas pathogenesis

    J. Neurochem.

    (2019)
  • Y. Peng et al.

    The role of MicroRNAs in human cancer

    Signal Transduct. Target. Ther.

    (2016)
  • M.N. Poy et al.

    A pancreatic islet-specific microRNA regulates insulin secretion

    Nature

    (2004)
  • M.H. Pourhanifeh et al.

    MicroRNAs and exosomes: small molecules with big actions in multiple myeloma pathogenesis

    IUBMB Life

    (2019)
  • J. Lu et al.

    MicroRNA expression profiles classify human cancers

    Nature

    (2005)
  • J. Sadri Nahand et al.

    Pathogenic role of exosomes and microRNAs in HPV-mediated inflammation and cervical cancer: a review

    Int. J. Cancer

    (2020)
  • C. Yang et al.

    microRNA-191 regulates endometrial cancer cell growth via TET1-mediated epigenetic modulation of APC

    J. Biochem.

    (2020)
  • G. Calabrese et al.

    miR-19a is involved in progression and malignancy of anaplastic thyroid Cancer cells

    Onco. Ther.

    (2019)
  • D. Shi et al.

    Upregulation of miR-153 inhibits triple-negative breast Cancer progression by targeting ZEB2-Mediated EMT and contributes to better prognosis

    Onco. Ther.

    (2019)
  • P. Zhou et al.

    MicroRNA-665 promotes the proliferation of ovarian cancer cells by targeting SRCIN1

    Exp. Ther. Med.

    (2020)
  • C. Yang et al.

    Silencing of microRNA-517a induces oxidative stress injury in melanoma cells via inactivation of the JNK signaling pathway by upregulating CDKN1C

    Cancer Cell Int.

    (2020)
  • J.Y. Chen et al.

    MiRNA-215-5p alleviates the metastasis of prostate cancer by targeting PGK1

    Eur. Rev. Med. Pharmacol. Sci.

    (2020)
  • X. Zou et al.

    MicroRNA-708 suppresses cell proliferation and enhances chemosensitivity of cervical Cancer cells to cDDP by negatively targeting timeless

    Onco. Ther.

    (2020)
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