Knockdown of Long Non-Coding RNA XIST Inhibited Doxorubicin Resistance in Colorectal Cancer by Upregulation of miR-124 and Downregulation of SGK1

Abstract

Background/Aims: Doxorubicin (DOX) is a widely used chemotherapeutic agent for colorectal cancer (CRC). However, the acquirement of DOX resistance limits its clinical application for cancer therapy. Mounting evidence has suggested that aberrantly expressed lncRNAs contribute to drug resistance of various tumors. Our study aimed to explore the role and molecular mechanisms of lncRNA X-inactive specific transcript (XIST) in chemoresistance of CRC to DOX. Methods: The expressions of XIST, miR-124, serum and glucocorticoid-inducible kinase 1 (SGK1) mRNA in DOX-resistant CRC tissues and cells were detected by qRT-PCR or western blot analysis. DOX sensitivity was assessed by detecting IC50 value of DOX, the protein levels of P-glycoprotein (P-gp) and glutathione S-transferase-π (GST-π) and apoptosis. The interactions between XIST, miR-124 and SGK1 were confirmed by luciferase reporter assay, qRT-PCR and western blot. Xenograft tumor assay was used to verify the role of XIST in DOX resistance in CRC in vivo. Results: XIST expression was upregulated and miR-124 expression was downregulated in DOX-resistant CRC tissues and cells. Knockdown of XIST inhibited DOX resistance of CRC cells, as evidenced by the reduced IC50 value of DOX, decreased P-gp and GST-π levels and enhanced apoptosis in XIST-silenced DOX-resistant CRC cells. Additionally, XIST positively regulated SGK1 expression by interacting with miR-124 in DOX-resistant CRC cells. miR-124 suppression strikingly reversed XIST-knockdown-mediated repression on DOX resistance in DOX-resistant CRC cells. Moreover, SGK1-depletion-elicited decrease of DOX resistance was greatly restored by XIST overexpression or miR-124 inhibition in DOX-resistant CRC cells. Furthermore, XIST knockdown enhanced the anti-tumor effect of DOX in CRC in vivo. Conclusion: XIST exerted regulatory function in resistance of DOX possibly through miR-124/SGK1 axis, shedding new light on developing promising therapeutic strategy to overcome chemoresistance in CRC patients.

<p>HNF1A-AS1 Regulates Cell Migration, Invasion and Glycolysis via Modulating miR-124/MYO6 in Colorectal Cancer Cells</p>

“…36,37 A previous study determined that miR-124 was downregulated in CRC and inhibited cell proliferation and drug resistance. [37][38][39] More than that, MYO6 has been verified to highly express in many cancers, such as prostate cancer, CRC, breast cancer and gastric cancer, which also participated in cell progression. [40][41][42][43] In our study, consistent with a previous study, miR-124 expressed low and MYO6 expressed high in CRC tissues and cells, and rescue experiments confirmed the effects of HNF1A-AS1 on cell migration and invasion through targeting miR-124/ MYO6 axis.…”

<p>Long non-coding RNA XIST promotes malignant behavior of epithelial ovarian cancer</p>

“…7 Moreover, XIST is also known to participate in the progression of several malignant solid tumors, such as gastric cancer, colorectal cancer, retinoblastoma, lung cancer, and liver cancer. [8][9][10][11][12] However, research related to XIST and EOC has been rarely carried out. In this study, we aimed to elucidate the role of XIST in EOC using EOC tissues and cell lines.…”

Emerging Roles of lncRNAs in the Formation and Progression of Colorectal Cancer

“…In tissues and cells of oxaliplatin-resistant CRC, lncRNA cancer susceptibility 15 (CASC15) is overexpressed, whereas its knockdown restores the sensitivity of HT29 and HCT116 to oxaliplatin (102). Knockout of lncRNA X inactive-specific transcript (XIST) inhibits resistance to DOX in CRC by up-regulating miR-124 and downregulating serum and glucocorticoid-inducible kinase 1 (103). The level of XIST is markedly upregulated in CRC of DOX resistance, while the level of miR-124 is reversed (103).…”

“…Knockout of lncRNA X inactive-specific transcript (XIST) inhibits resistance to DOX in CRC by up-regulating miR-124 and downregulating serum and glucocorticoid-inducible kinase 1 (103). The level of XIST is markedly upregulated in CRC of DOX resistance, while the level of miR-124 is reversed (103). In CRC cell lines, knockout of lncRNA Hotair and upregulation of miR-203a-3p lead to restrain of cellular proliferation and reduce resistance to cisplatin (63).…”