LncRNA LIMT (LINC01089) contributes to sorafenib chemoresistance via regulation of miR-665 and epithelial to mesenchymal transition in hepatocellular carcinoma cells

Jing Sun; Xiaoxiao Zheng; Baoming Wang; Ying Cai; Li Zheng; Liqiang Hu; Xuemei Lu; Shangzhi Xie; Xin Zhang; Hao Liu; Longyun Ye

doi:10.3724/abbs.2021019

LncRNA LIMT (LINC01089) contributes to sorafenib chemoresistance via regulation of miR-665 and epithelial to mesenchymal transition in hepatocellular carcinoma cells

Acta Biochim Biophys Sin (Shanghai). 2022 Jan 25;54(2):261-270. doi: 10.3724/abbs.2021019.

Authors

Jing Sun¹, Xiaoxiao Zheng², Baoming Wang², Ying Cai², Li Zheng², Liqiang Hu², Xuemei Lu², Shangzhi Xie², Xin Zhang³, Hao Liu², Longyun Ye⁴

Affiliations

¹ Department of Gastrointestinal Surgery, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, China.
² Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China.
³ Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310006, China.
⁴ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.

Abstract

Hepatocellular carcinoma (HCC) is one of the most malignant tumors worldwide and HCC patients often develop drug resisitene. Long non-coding RNAs (LncRNAs) are closely related to cell cycle, growth, development, differentiation, and apoptosis. Abnormally expressed lncRNAs have been proved to mediate drug resistance in tumor cells. However, the effect of LIMT on drug resistance has not been explored in HCC. In this study, we explored the effect of long non-coding RNA LIMT on drug resistance and its underlying mechanism in hepatocellular carcinoma (HCC). Our results showed that LncRNA LINC01089 (LIMT) expression is downregulated in 78.57% (44/56) of 56 HCC tumor tissue samples. LIMT expression is also downregulated in HCC cells compared with that in normal liver LO2 cells. Inhibition of LIMT increases the resistance to sorafenib and promotes cell invasion via regulation of epithelial to mesenchymal transition (EMT) in HCC. StarBase V3.0 was used to predict the potential binding site of miR-665 in . Furthermore, miR-665 participates in sorafenib resistance and also regulates the level of EMT-related proteins in HCC cells. A rescue experiment demonstrated that silencing of eliminats the inhibitory effect of the miR-665 inhibitor on sorafenib resistance in HCC cells. Taken together, our findings revealed that downregulation of LIMT increases the resistance of HCC to sorafenib via miR-665 and EMT. Therefore, LIMT, which serves as a therapeutically effective target, will provide new hope for the treatment of HCC.

Keywords: EMT; HCC; LncRNA LIMT; chemoresistance; sorafenib.

MeSH terms

Carcinoma, Hepatocellular* / drug therapy
Carcinoma, Hepatocellular* / genetics
Carcinoma, Hepatocellular* / metabolism
Cell Line, Tumor
Cell Proliferation
Drug Resistance, Neoplasm / genetics
Epithelial-Mesenchymal Transition / genetics
Gene Expression Regulation, Neoplastic
Humans
Liver Neoplasms* / drug therapy
Liver Neoplasms* / genetics
Liver Neoplasms* / metabolism
MicroRNAs* / genetics
MicroRNAs* / metabolism
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
Sorafenib / pharmacology
Sorafenib / therapeutic use

Substances

MIRN665 microRNA, human
MicroRNAs
RNA, Long Noncoding
Sorafenib

Grants and funding

This work was supported by the grants from the Medical and Health Research Project of Zhejiang Province (No. 2018KY126 to L.Y.), Wenzhou Municipal Science and Technology Bureau (No. Y20170095 to L.Y.), and Zhejiang Provincial Natural Science Foundation of China (No. LQ19H280008 to X.Z.).