ReviewAutophagy-related microRNAs: Possible regulatory roles and therapeutic potential in and gastrointestinal cancers
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)
- et al.
Trends in cancer mortality in the elderly in Japan, 1970-2007
Ann. Oncol.
(2010) - et al.
The relevance of gastric cancer biomarkers in prognosis and pre- and post- chemotherapy in clinical practice
Biomed. Pharmacother.
(2017) MicroRNAs: target recognition and regulatory functions
Cell
(2009)- et al.
The role of autophagy induced by tumor microenvironment in different cells and stages of cancer
Cell Biosci.
(2015) - et al.
Autophagy in the pathogenesis of disease
Cell
(2008) - et al.
The C. Elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14
Cell
(1993) MicroRNAs: genomics, biogenesis, mechanism, and function
Cell
(2004)- et al.
Bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila
Cell
(2003) - et al.
Pestell RG: microRNA, cell cycle, and human breast cancer
Am. J. Pathol.
(2010) - et al.
MicroRNAs in cancer: biomarkers, functions and therapy
Trends Mol. Med.
(2014)
miR-124 regulates EMT based on ZEB2 target to inhibit invasion and metastasis in triple-negative breast cancer
Pathol. Res. Pract.
MicroRNA-135a promotes proliferation, migration, invasion and induces chemoresistance of endometrial cancer cells
European journal of obstetrics & gynecology and reproductive biology: X
The role of the Atg1/ULK1 complex in autophagy regulation
Curr. Opin. Cell Biol.
Autophagy: cancer’s friend or foe?
Adv. Cancer Res.
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.
Regulation of autophagy by miR-30d impacts sensitivity of anaplastic thyroid carcinoma to cisplatin
Biochem. Pharmacol.
Autophagy regulation and its role in gastric cancer and colorectal cancer
Cancer Biomark.
Novel role of miR-133a-3p in repressing gastric cancer growth and metastasis via blocking autophagy-mediated glutaminolysis
J. Exp. Clin. Cancer Res.
MIR-1265 regulates cellular proliferation and apoptosis by targeting calcium binding protein 39 in gastric cancer and, thereby, impairing oncogenic autophagy
Cancer Lett.
MiR-181a suppresses autophagy and sensitizes gastric cancer cells to cisplatin
Gene
Circular RNA circNRIP1 acts as a microRNA-149-5p sponge to promote gastric cancer progression via the AKT1/mTOR pathway
Mol. Cancer
METase promotes cell autophagy via promoting SNHG5 and suppressing miR-20a in gastric cancer
Int. J. Biol. Macromol.
Novel role of miR-133a-3p in repressing gastric cancer growth and metastasis via blocking autophagy-mediated glutaminolysis
J. Exp. Clin. Cancer Res.
MicroRNA-148a-3p enhances cisplatin cytotoxicity in gastric cancer through mitochondrial fission induction and cyto-protective autophagy suppression
Cancer Lett.
The microRNA-423-3p-Bim axis promotes cancer progression and activates oncogenic autophagy in gastric cancer
Mol. Ther.
MicroRNA-143 enhances chemosensitivity of Quercetin through autophagy inhibition via target GABARAPL1 in gastric cancer cells
Biomed. Pharmacother.
Cancer statistics, 2009
CA Cancer J. Clin.
Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries
CA Cancer J. Clin.
Clinical outcomes after surgical resection of colorectal cancer in 1,294 patients
Hepatogastroenterology
Radiotherapy versus surgery within multimodality protocols for esophageal cancer--a meta-analysis of the randomized trials
Cancer Treat. Rev.
Clinical relevance of circulating cell-free microRNAs in cancer
Nat. Rev. Clin. Oncol.
Modulation of inflammation by autophagy: consequences for human disease
Autophagy
Autophagy in vascular disease
Circ. Res.
Compromised autophagy and neurodegenerative diseases
Nat. Rev. Neurosci.
Autophagy in cellular metabolism and cancer
J. Clin. Invest.
Non-coding RNAs in human disease
Nat. Rev. Genet.
microRNAs: new prognostic, diagnostic, and therapeutic biomarkers in cervical cancer
J. Cell. Physiol.
Genetic and epigenetic contribution to astrocytic gliomas pathogenesis
J. Neurochem.
The role of MicroRNAs in human cancer
Signal Transduct. Target. Ther.
A pancreatic islet-specific microRNA regulates insulin secretion
Nature
MicroRNAs and exosomes: small molecules with big actions in multiple myeloma pathogenesis
IUBMB Life
MicroRNA expression profiles classify human cancers
Nature
Pathogenic role of exosomes and microRNAs in HPV-mediated inflammation and cervical cancer: a review
Int. J. Cancer
microRNA-191 regulates endometrial cancer cell growth via TET1-mediated epigenetic modulation of APC
J. Biochem.
miR-19a is involved in progression and malignancy of anaplastic thyroid Cancer cells
Onco. Ther.
Upregulation of miR-153 inhibits triple-negative breast Cancer progression by targeting ZEB2-Mediated EMT and contributes to better prognosis
Onco. Ther.
MicroRNA-665 promotes the proliferation of ovarian cancer cells by targeting SRCIN1
Exp. Ther. Med.
Silencing of microRNA-517a induces oxidative stress injury in melanoma cells via inactivation of the JNK signaling pathway by upregulating CDKN1C
Cancer Cell Int.
MiRNA-215-5p alleviates the metastasis of prostate cancer by targeting PGK1
Eur. Rev. Med. Pharmacol. Sci.
MicroRNA-708 suppresses cell proliferation and enhances chemosensitivity of cervical Cancer cells to cDDP by negatively targeting timeless
Onco. Ther.
Cited by (51)
MicroRNA-155 and cancer metastasis: Regulation of invasion, migration, and epithelial-to-mesenchymal transition
2023, Pathology Research and PracticeSystemic lupus erythematosus: From non-coding RNAs to exosomal non-coding RNAs
2023, Pathology Research and PracticeProstate cancer and microRNAs: New insights into apoptosis
2023, Pathology Research and PracticeAutophagy: Dual roles and perspective for clinical treatment of colorectal cancer
2023, BiochimieCitation Excerpt :Furthermore, the role of autophagy in CRC is currently unclear and comprehensive mechanistic studies need to be conducted. MicroRNAs (miRNAs) are short non-protein coding RNA that regulate the expression of their target genes by binding to the 3ʹ untranslated region (UTR) of target mRNAs [100,101]. Recent evidence has demonstrated that miRNAs participate in autophagy in tumor cells and are directly involved in cancer progression as well as resistance to chemotherapies (Table 1 and Fig. 2) [100,102].
Neutrophil mediated drug delivery for targeted glioblastoma therapy: A comprehensive review
2022, Biomedicine and PharmacotherapyDNA damage response and repair in the development and treatment of brain tumors
2022, European Journal of Pharmacology