Novel role of lncRNA CHRF in cisplatin resistance of ovarian cancer is mediated by miR-10b induced EMT and STAT3 signaling

Abstract

Ovarian Cancer (OC) is a highly lethal gynecological cancer which often progresses through acquired resistance against the administered therapy. Cisplatin is a common therapeutic for the treatment of OC patients and therefore it is critical to understand the mechanisms of resistance against this drug. We studied a paired cell line consisting of parental and cisplatin resistant (CR) derivative ES2 OC cells, and found a number of dysregulated lncRNAs, with CHRF being the most significantly upregulated lncRNA in CR ES2 cells. The findings corroborated in human patient samples and CHRF was significantly elevated in OC patients with resistant disease. CHRF was also found to be elevated in patients with liver metastasis. miR-10b was found to be mechanistically involved in CHRF mediated cisplatin resistance. It induced resistance in not only ES2 but also OVCAR and SKOV3 OC cells. Induction of epithelial-to-mesenchymal-transition (EMT) and activation of STAT3 signaling were determined to be the mechanisms underlying the CHRF-miR-10b axis-mediated cisplatin resistance. Down-regulation of CHRF reversed EMT, STAT3 activation and the resulting cisplatin resistance, which could be attenuated by miR-10b. The results were also validated in an in vivo cisplatin resistance model wherein CR cells were associated with increased tumor burden, CHRF downregulation associated with decreased tumor burden and miR-10b again attenuated the CHRF downregulation effects. Our results support a novel role of lncRNA CHRF in cisplatin resistance of OC and establish CHRF-miR-10b signaling as a putative therapeutic target for sensitizing resistant OC cells.

HOTTIP-miR-205-ZEB2 Axis Confers Cisplatin Resistance to Ovarian Cancer Cells

“…HOXD-AS1 (Chi et al, 2018), PANDAR (Wang et al, 2018), CASC11 (Shen et al, 2019), LINC00152 (Zou and Li, 2019), NCK1-AS1 (Chang et al, 2020), LINC01125 (Guo and Pan, 2019), CCAT1 (Wang D.Y. et al, 2020), NEAT1 (Zhu et al, 2020), CHRF (Tan et al, 2020), ZEB1-AS1 (Dai et al, 2021), TRPM2-AS (Ding et al, 2021), and LOC102724169 (Zhou et al, 2021). While these studies are a testimony to the potential of lncRNAs as modulators of cisplatin resistance, the work has not yet resulted in any clinically relevant therapies.…”

miR-4461 Regulates the Proliferation and Metastasis of Ovarian Cancer Cells and Cisplatin Resistance

“…Moreover, PTEN siRNA could eliminate the distinct proliferation capacity or metastasis ability between miR-4461 overexpression OC cells and control cells. Acquired cisplatin resistance is a serious problem for the therapy of OC patients (8,24). miRNAs actually participated in the regulation of tumorigenesis and drug resistance in OC (11,25).…”

“…Acquired cisplatin resistance is a serious problem for the therapy of OC patients ( 8 , 24 ). miRNAs actually participated in the regulation of tumorigenesis and drug resistance in OC ( 11 , 25 ).…”

“…More than 70% advanced OC patients will recur after surgery ( 5 ). The therapy based on th Cisplatin is one of the first-line treatment for OC patients, while most patients develop resistance after a period of medication ( 6 – 8 ). Therefore, it's pressing to explore the potential mechanism of OC and uncover new treatment target to improve the prognosis of OC patients.…”

Long noncoding RNA HULC contributes to paclitaxel resistance in ovarian cancer via miR-137/ITGB8 axis

“…Wang et al indicated that colon cancer-associated transcript 1 (CCAT1) acted as a miRNA sponge for miR-454 to regulate Survivin expression, thereby enhancing the cisplatin resistance of OC cells [ 10 ]. Besides, downregulation of CHRF reversed the activation of epithelial-to-mesenchymal-transition (EMT) and STAT3 signaling and then improved the sensitivity of OC cells to cisplatin [ 11 ]. lncRNA highly upregulated in liver cancer (HULC), located in chromosome 6p24.3, was reported to be aberrantly elevated in several tumors, including human pancreatic cancer [ 12 ], gastric cancer [ 13 ], osteosarcoma [ 14 ], and OC [ 15 ].…”