Autophagy Inhibition and Sensitization to Cisplatin in Esophageal Cancer Stem-Like Cells via All-trans Retinoic Acid-induced miR-30a.

Abstract

Providing insights into the chemoresistance of esophageal squamous cell carcinoma (ESCC) and its dependence on chemotherapy-induced autophagy. Autophagy is induced during chemotherapy of cancer cells, promoting resistance to anti-cancer treatments. The objective of this study is to investigate the modulation of microRNA-30a (miR-30a), a known regulator of autophagy, in ESCC cells by all-trans retinoic acid (ATRA). Treatment involved ESCC cells KYSE-30 and TE8 with cis-dichloro-diamine platinum (CDDP), enriching CDDP-surviving cells (CDDP-SCs). qRT-PCR and dual luciferase reporter assay (DLRA) were employed to evaluate miR-30a expression and its interaction with Beclin-1 (BECN1) in both CDDP-SCs and those treated with ATRA. Chemotherapy using CDDP led to a significant decrease in miR-30a expression within ESCC cells. Increased autophagy levels were identified in cancer cells exhibiting stem cell-like properties, characterized by the overexpression of specific stem cell markers. These results suggest that the downregulation of miR-30a induced by CDDP treatment may represent a potential underlying mechanism for increased autophagic activity, as evidenced by the upregulation of autophagy-related proteins, such as BECN1 and an elevated LC3-II/LC3-I ratio. ATRA treatment elevated miR-30a expression and disrupted hallmark cancer stem cell (CSC) features in ESCC cells. Further investigations demonstrated that increased miR-30a expression led to a reduction in the expression of its target gene, BECN1, and attenuated BECN1-mediated autophagy. This resulted in an augmentation of CDDP-induced apoptosis in ESCC cells and a G2/M cell cycle arrest. CDDP chemotherapy reduced miR-30a, promoting ESCC cell resistance through autophagy and CSC-like features, a process that may be modulated by ATRA.