Role of miR-138 in drug resistance and signaling pathway of different types of cancer

Role of miR-138 in drug resistance and signaling pathway of different types of cancer
Mahtab Kadkhodayi,¹ Reza Safaralizadeh,^2,* Behzad Baradaran,³ Vahid Asghariazar ,⁴
1. Department of Animal Biology, Faculty of Natural Sciences, The University of Tabriz, Tabriz, Iran
2. Department of Animal Biology, Faculty of Natural Sciences, The University of Tabriz, Tabriz, Iran
3. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
4. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
Introduction: MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules (19-22 nucleotides in length) that regulate the expression of target genes either through translational inhibition or destabilization of mRNA by direct interaction with the 3′untranslated regions (3′-UTRs) of target mRNAs. Notably, due to miRNAs crucial roles in controlling diverse metabolic and cellular biological processes, aberrant their expression could potentially develop into cancers. MiR-138 originates from two primary transcripts, pri-miR-138-1, and pri-miR-138-2 as encoded on chromosomes 3 (3p21) and 16 (16q13), which form the mature miR-138. Changes in miR-138 expression can affect cell proliferation, apoptosis, invasion, metastatic ability, and drug resistance of numerous cancer cells. Besides, miR-138 has been expressed at a low level in many types of human cancer and could function as a tumor suppressor by negatively regulating oncogenes. Interestingly, it was observed only in brain tumors that miR-138 could function as an oncogenic miR in a certain type of brain tumor cells. Moreover, downregulation of miR-138 is involved in the chemoresistance of several cancer types, including prostate, gastric and non-small cell lung cancer, multiple myeloma, renal cell carcinoma, and osteosarcoma. MiR-138 could induce apoptosis and reverse drug resistance of cancer cells by targeting multiple genes involved in multiple processes such as drug transport, drug metabolism, DNA repair, cell survival, and apoptosis. Overexpression of miR-138 in cancer cells could significantly enhance their sensitivity to apoptosis and cell death induced by chemotherapeutic drugs. Besides, it might potentially be used as a combination therapy agent with other therapy methods. Mirna-138 is involved in the pathogenesis and chemoresistance of cancers by directly targeting several mRNAs such as FAK, GPR124, ERCC1, ERCC4, vimentin, H2AX, EZH2, EGFR, K2, and BIM. This article reviews the expression and functional role of miR-138 in various human cancers with its target genes and pathways in a hope to find a better therapeutic option to treat human cancers and highlights potential therapeutic targets for reversing miRNA-mediated drug resistance.
Methods: Original articles and different databases such as PubMed and Google Scholar have been used to write the present review article.
Results: Evidence supports that miR-138 acts as a tumor suppressor and regulates various downstream effectors associated with cancer. However, the oncogenic role of miR-138 was observed in rare cases of brain tumors. The dysregulated miR-138 has been shown to affect the hallmarks of cancer, including sustaining proliferative signaling, evading growth suppressors, resisting cell death, and activating invasion and metastasis. Furthermore, miR‑138 affects the chemotherapeutic sensitivity of several human cancer types. More importantly, accumulating evidence has shown that miR-138, as other miRNAs, can regulate multiple targets in can¬cer cells. These findings make miR-138 as an attractive therapeutic option to treat human cancers.
Conclusion: The growing knowledge about the miR-138 impact on several aspects of carcinogenesis and its meaning for therapeutic usage implicates miR-138 to be a promising candidate for response prediction, control, and modification of conventional and/or new developed anticancer treatments. Thus, it is hypothesized that a replacement treatment with miR-138 mimics could be a promising strategy for cancers characterized by downregulation of miR-138. However, there is a need to develop more efficient delivery systems. More important, several studies demonstrated that miR-138 could successfully modulate the sensitivity of cells to well known chemotherapeutic agents. These data point out the immense prospect of using miR-138 in combination with existing therapeutic strategies to maximize the effect of cancer treatment and to improve the survival of patients. Further studies are required prior to implementing miRNA-based cancer therapeutic strategies into clinical practice.
Keywords: MicroRNA; Gene regulation; Apoptosis, Metastasis