MicroRNA-410 regulates autophagy-related gene ATG16L1 expression and enhances chemosensitivity via autophagy inhibition in osteosarcoma

Abstract

Osteosarcoma, which is the most common type of primary bone tumor in adolescents, is characterized by complex genetic alterations and frequent resistance to conventional treatments. MicroRNAs (miRs) have emerged as fundamental regulators in gene expression through their ability to silence gene expression at post-transcriptional and translational levels. The present study investigated the role of miR-410 in the progression of osteosarcoma. The results demonstrated that the expression of miR-410 was markedly downregulated in human osteosarcoma tissues, and U2OS and MG-63 osteosarcoma cell lines. Clinicopathological significance suggested that miR-410 may be a potential biomarker for chemotherapy-resistant osteosarcoma. Furthermore, overexpression of miR-410 exhibited a limited effect on cell viability in U2OS and MG-63 cells. Target prediction algorithms (TargetScan and miRanda) indicated that autophagy related 16-like 1 (ATG16L1) was a potential target gene of miR-410. A luciferase reporter assay demonstrated that miR-410 directly decreased ATG16L1 expression by targeting its 3′-untranslated region. In addition, the results revealed that miR-410 was able to markedly inhibit autophagy. Accordingly, autophagy was activated as a protective mechanism when osteosarcoma cells were exposed to three common anticancer drugs, including rapamycin, doxorubicin and cisplatin. Furthermore, the autophagy inhibitor 3-methyladenine and miR-410 expression were able to improve the therapeutic response of the cells to chemotherapy drugs (rapamycin, doxorubicin and cisplatin), thus indicating that miR-410 enhanced chemosensitivity through autophagy inhibition in osteosarcoma cells. In conclusion, studies regarding the function of miR-410 on autophagy provided insight into the biological function of miR-410 in osteosarcoma and may offer a promising approach for the treatment of osteosarcoma.

Emerging roles of let‑7d in attenuating pulmonary arterial hypertension via suppression of pulmonary artery endothelial cell autophagy and endothelin synthesis through ATG16L1 downregulation

“…For example, miR-30d has been found to suppress autophagy in human cancer cells by inhibiting autophagy pathway-related genes, such as ATG12, ATG5 and ATG2; autophagosome formation; and the conversion of Lc3B-I to Lc3B-II (36). Furthermore, ATG16L1 plays an important role in autophagy and a previous study verified that suppression of autophagy by miR-410 overexpression in osteosarcoma cells was achieved partly through downregulation of ATG16L1 (17). Importantly, Xu et al (37) found that ATG4B is an underlying target gene of let-7i and that overexpression of let-7i could inhibit autophagic activity in preeclampsia through downregulation of ATG4B.…”

“…In addition, autophagy-related 16-like 1 (ATG16L1) has been identified as an autophagy-related gene that can regulate autophagosomes (16). ATG16L1 belongs to a class of protein complexes that are considered vital for autophagy (17). Emerging data has illustrated the functionality of ATG16L1 in the development of atherogenesis (18).…”

Expression and Clinical Implication of Autophagy-Associated Protein p62 in Osteosarcoma

“…In cisplatin-resistant osteosarcoma cells, chloroquine could block autophagy and increase chemosensitivity [43]. Autophagy inhibitor 3-MA combined with doxorubicin or cisplatin could improve the therapeutic response to chemotherapy drugs in U2OS, Sao-2, and MG63 osteosarcoma cell lines [10, 44]. Therefore, enhancing the level of p62 may be an effective therapy for cancer treatment.…”

Downregulation of microRNA-95-3p suppresses cell growth of osteosarcoma via CDKN1A/p21 expression

“…MicroRNAs (miRNAs) are a type of non-coding RNAs with regulatory function and a length of approximately 20-25 nucleotides, which identify target mRNAs according to the principle of complementary base pairing and guide silencing complex to degrade target mRNAs or repress translation of mRNAs (5). Increasing studies found that miRNAs played an important role in specific cellular processes such as cell differentiation, morphosis and neoplasia (6). In human cancer, a miRNA can be an oncogene or a cancer suppressor gene in the process of tumorigenesis.…”