LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner.
Long non-coding RNAs (lncRNAs) are known to play important roles in different cell contexts, including cancers. However, little is known about lncRNAs in cholangiocarcinoma (CCA), a cholangiocyte malignancy with poor prognosis, associated with chronic inflammation and damage to the biliary epithelium. The aim of the study is to identify if any lncRNA might associate with inflammation or oxidative stress in CCA and regulate the disease progression.



In this study, RNA-seqs datasets were used to identify aberrantly expressed lncRNAs. Small interfering RNA and overexpressed plasmids were used to modulate the expression of lncRNAs, and luciferase target assay RNA immunoprecipitation (RIP) was performed to explore the mechanism of miRNA-lncRNA sponging.



We firstly analyzed five available RNA-seqs datasets to investigate aberrantly expressed lncRNAs which might associate with inflammation or oxidative stress. We identified that two lncRNAs, H19 and HULC, were differentially expressed among all the samples under the treatment of hypoxic or inflammatory factors, and they were shown to be stimulated by short-term oxidative stress responses to H2O2and glucose oxidase in CCA cell lines. Further studies revealed that these two lncRNAs promoted cholangiocyte migration and invasion via the inflammation pathway. H19 and HULC functioned as competing endogenous RNAs (ceRNAs) by sponging let-7a/let-7b and miR-372/miR-373, respectively, which activate pivotal inflammation cytokine IL-6 and chemokine receptor CXCR4.



Our study revealed that H19 and HULC, up-regulated by oxidative stress, regulate CCA cell migration and invasion by targeting IL-6 and CXCR4 via ceRNA patterns of sponging let-7a/let-7b and miR-372/miR-373, respectively. The results suggest that these lncRNAs might be the chief culprits of CCA pathogenesis and progression. The study provides new insight into the mechanism linking lncRNA function with CCA and may serve as novel targets for the development of new countermeasures of CCA.
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, 510275, People's Republic of China.
Wen-Tao
WT
Wang
Department of Hepatobiliary, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, People's Republic of China.|Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, People's Republic of China.
Hua
H
Ye
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, 510275, People's Republic of China.
Pan-Pan
PP
Wei
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, 510275, People's Republic of China.
Bo-Wei
BW
Han
Department of Hepatobiliary, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, People's Republic of China.|Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, People's Republic of China.
Bo
B
He
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, 510275, People's Republic of China.
Zhen- Hua
ZH
Chen
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, 510275, People's Republic of China. lsscyq@mail.sysu.edu.cn.
Yue-Qin
YQ
Chen
D045744:Cell Line, Tumor; D002465:Cell Movement; D018281:Cholangiocarcinoma / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000235:genetics; D009361:Neoplasm Invasiveness; D018384:Oxidative Stress / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000378:metabolism* / Q000502:physiology; D019718:Receptors, CXCR4 / Q000235:genetics
C527276:CXCR4 protein, human; C094335:H19 long non-coding RNA; C574685:HULC long non-coding RNA, human; C508600:IL6 protein, human; D015850:Interleukin-6; D062085:RNA, Long Noncoding; D019718:Receptors, CXCR4
Cholangiocarcinoma; Inflammation response; Migration and invasion; Oxidative stress; ceRNA