LncRNA FOXD2‐AS1 as a competitive endogenous RNA against miR‐150‐5p reverses resistance to sorafenib in hepatocellular carcinoma

The current study elucidated the role of a long non‐coding RNA (lncRNA), FOXD2‐AS1, in the pathogenesis of hepatocellular carcinoma (HCC) and the regulatory mechanism underlying FOXD2‐AS1/miR‐150‐5p/transmembrane protein 9 (TMEM9) signalling in HCC. Microarray analysis was used for preliminary screening of candidate lncRNAs in HCC tissues. qRT‐PCR and Western blot analyses were used to detect the expression of FOXD2‐AS1. Cell proliferation assays, luciferase assay and RNA immunoprecipitation were performed to examine the mechanism by which FOXD2‐AS1 mediates sorafenib resistance in HCC cells. FOXD2‐AS1 and TMEM9 were significantly decreased and miR‐150‐5p was increased in SR‐HepG2 and SR‐HUH7 cells compared with control parental cells. Overexpression of FOXD2‐AS1 increased TMEM9 expression and overcame the resistance of SR‐HepG2 and SR‐HUH7 cells. Conversely, knockdown of FOXD2‐AS1 decreased TMEM9 expression and increased the sensitivity of HepG2 and Huh7 cells to sorafenib. Our data also demonstrated that FOXD2‐AS1 functioned as a sponge for miR‐150‐5p to modulate TMEM9 expression. Taken together, our findings revealed that FOXD2‐AS1 is an important regulator of TMEM9 and contributed to sorafenib resistance. Thus, FOXD2‐AS1 may serve as a therapeutic target against sorafenib resistance in HCC.

[1]  Qingling Li,et al.  The functional pathway analysis and clinical significance of miR-20a and its related lncRNAs in breast cancer. , 2018, Cellular signalling.

[2]  R. Pei,et al.  Long non‐coding RNA AFAP1‐AS1/miR‐320a/RBPJ axis regulates laryngeal carcinoma cell stemness and chemoresistance , 2018, Journal of cellular and molecular medicine.

[3]  Qing An,et al.  Long noncoding RNA FOXD2-AS1 accelerates the gemcitabine-resistance of bladder cancer by sponging miR-143. , 2018, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[4]  C. Kanduri,et al.  PAN-cancer analysis of S-phase enriched lncRNAs identifies oncogenic drivers and biomarkers , 2018, Nature Communications.

[5]  Hu YiRen,et al.  Long noncoding RNA MALAT1 regulates autophagy associated chemoresistance via miR-23b-3p sequestration in gastric cancer , 2017, Molecular Cancer.

[6]  Qiong Chen,et al.  Microarray data re-annotation reveals specific lncRNAs and their potential functions in non-small cell lung cancer subtypes , 2017, Molecular medicine reports.

[7]  Y. Xiong,et al.  Effects of TMEM9 gene on cell progression in hepatocellular carcinoma by RNA interference. , 2016, Oncology reports.

[8]  M. Vinciguerra,et al.  DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression. , 2016, Cancer research.

[9]  J. Wang,et al.  STAT1 inhibits human hepatocellular carcinoma cell growth through induction of p53 and Fbxw7 , 2015, Cancer Cell International.

[10]  Ming Sun,et al.  Long non-coding RNA TUG1 is up-regulated in hepatocellular carcinoma and promotes cell growth and apoptosis by epigenetically silencing of KLF2 , 2015, Molecular Cancer.

[11]  F. Xia,et al.  A high baseline HBV load and antiviral therapy affect the survival of patients with advanced HBV‐related HCC treated with sorafenib , 2015, Liver international : official journal of the International Association for the Study of the Liver.

[12]  I. Ng,et al.  Nuclear factor kappa B–mediated CD47 up‐regulation promotes sorafenib resistance and its blockade synergizes the effect of sorafenib in hepatocellular carcinoma in mice , 2015, Hepatology.

[13]  Xiaoying Huang,et al.  Circulating Hepatocellular Carcinoma Cells are Characterized by CXCR4 and MMP26 , 2015, Cellular Physiology and Biochemistry.

[14]  Jun Lu,et al.  Low Expression of miR-448 Induces EMT and Promotes Invasion by Regulating ROCK2 in Hepatocellular Carcinoma , 2015, Cellular Physiology and Biochemistry.

[15]  Jian Huang,et al.  LEIGClong non-coding RNA acts as a tumor suppressor in gastric carcinoma by inhibiting the epithelial-to-mesenchymal transition , 2014, BMC Cancer.

[16]  M. Colombo,et al.  VEGF and VEGFR genotyping in the prediction of clinical outcome for HCC patients receiving sorafenib: The ALICE‐1 study , 2014, International journal of cancer.

[17]  Chang Xian Li,et al.  Identification of Transmembrane Protein 98 as a Novel Chemoresistance-Conferring Gene in Hepatocellular Carcinoma , 2014, Molecular Cancer Therapeutics.

[18]  G. Cao,et al.  Human cytidine deaminases facilitate hepatitis B virus evolution and link inflammation and hepatocellular carcinoma. , 2014, Cancer letters.

[19]  I. Rusyn,et al.  Role of epigenetic aberrations in the development and progression of human hepatocellular carcinoma. , 2014, Cancer letters.

[20]  C. Gao,et al.  MiR-200c sensitizes clear-cell renal cell carcinoma cells to sorafenib and imatinib by targeting heme oxygenase-1. , 2014, Neoplasma.

[21]  Yong Yang,et al.  The Noncoding RNA Expression Profile and the Effect of lncRNA AK126698 on Cisplatin Resistance in Non-Small-Cell Lung Cancer Cell , 2013, PloS one.

[22]  Xiaoyi Duan,et al.  The Noncytotoxic Dose of Sorafenib Sensitizes Bel-7402/5-FU Cells to 5-FU by Down-Regulating 5-FU-Induced Nrf2 Expression , 2013, Digestive Diseases and Sciences.

[23]  T. Kwok,et al.  Riboregulator H19 induction of MDR1-associated drug resistance in human hepatocellular carcinoma cells , 2007, Oncogene.