linc‑ROR facilitates hepatocellular carcinoma resistance to doxorubicin by regulating TWIST1‑mediated epithelial‑mesenchymal transition

Zhang,Yuanbiao; Wu,Weiding; Sun,Qiang; Ye,Longyun; Zhou,Dongkai; Wang,Weilin

doi:10.3892/mmr.2021.11979

linc‑ROR facilitates hepatocellular carcinoma resistance to doxorubicin by regulating TWIST1‑mediated epithelial‑mesenchymal transition

Authors:
- Yuanbiao Zhang
- Weiding Wu
- Qiang Sun
- Longyun Ye
- Dongkai Zhou
- Weilin Wang
View Affiliations

Affiliations: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China, Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
Published online on: March 9, 2021 https://doi.org/10.3892/mmr.2021.11979
Article Number: 340
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Long non‑coding RNAs are associated with cancer progression. Long intergenic non‑protein coding RNA (linc)‑regulator of reprogramming (ROR) enhances tumor development in hepatocellular carcinoma (HCC). However, the effect of chemoresistance and its underlying mechanisms in HCC are not completely understood. The present study aimed to identify the effect of ROR on sensitivity to doxorubicin (DOX) in HCC cells. In the present study, Cell Counting Kit‑8 and EdU assays were performed to assess cell viability and proliferation, respectively. In addition, E‑cadherin and vimentin protein expression levels were assessed via western blotting and immunofluorescence.The results of the present study demonstrated that HCC cells with high linc‑ROR expression levels were more resistant to DOX, and linc‑ROR knockdown increased HCC cell DOX sensitivity compared with the control group. The results indicated that compared with the NC siRNA group, linc‑ROR knockdown notably suppressed epithelial‑mesenchymal transition by downregulating twist family bHLH transcription factor 1 (TWIST1) expression. TWIST1 knockdown displayed a similar effect on HCC cell DOX sensitivity to linc‑ROR knockdown. Moreover, linc‑ROR knockdown‑induced HCC cell DOX sensitivity was inhibited by TWIST1 overexpression. The present study provided evidence that linc‑ROR promoted HCC resistance to DOX by inducing EMT via interacting with TWIST1. Therefore, linc‑ROR might serve as a therapeutic target for reducing DOX resistance in HCC.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
2	Song P, Cai Y, Tang H, Li C and Huang J: The clinical management of hepatocellular carcinoma worldwide: A concise review and comparison of current guidelines from 2001 to 2017. Biosci Trends. 11:389–398. 2017. View Article : Google Scholar : PubMed/NCBI
3	Ozer Etik D, Suna N and Boyacioglu AS: Management of hepatocellular carcinoma: Prevention, surveillance, diagnosis, and staging. Exp Clin Transplant. 15 (Suppl 2):S31–S35. 2017.
4	Kulik LM: Advancements in hepatocellular carcinoma. Curr Opin Gastroenterol. 23:268–274. 2007. View Article : Google Scholar : PubMed/NCBI
5	Clark T, Maximin S, Meier J, Pokharel S and Bhargava P: Hepatocellular carcinoma: Review of epidemiology, screening, imaging diagnosis, response assessment, and treatment. Curr Probl Diagn Radiol. 44:479–486. 2015. View Article : Google Scholar : PubMed/NCBI
6	Nishikawa H, Kita R, Kimura T and Osaki Y: Transcatheter arterial embolic therapies for hepatocellular carcinoma: A literature review. Anticancer Res. 34:6877–6886. 2014.PubMed/NCBI
7	Pastorelli D, Cartei G, Zustovich F, Marchese F, Artioli G, Zovato S, Binato S, Ceravolo R, Cingarlini S, Salmaso F, et al: Gemcitabine and liposomal doxorubicin in biliary and hepatic carcinoma (HCC) chemotherapy: Preliminary results and review of the literature. Ann Oncol. 17 (Suppl 5):v153–v157. 2006. View Article : Google Scholar : PubMed/NCBI
8	Yang JX, Rastetter RH and Wilhelm D: Non-coding RNAs: An introduction. Adv Exp Med Biol. 886:13–32. 2016. View Article : Google Scholar : PubMed/NCBI
9	Wei L, Wang X, Lv L, Liu J, Xing H, Song Y, Xie M, Lei T, Zhang N and Yang M: The emerging role of microRNAs and long noncoding RNAs in drug resistance of hepatocellular carcinoma. Mol Cancer. 18:1472019. View Article : Google Scholar : PubMed/NCBI
10	Kondo Y, Shinjo K and Katsushima K: Long non-coding RNAs as an epigenetic regulator in human cancers. Cancer Sci. 108:1927–1933. 2017. View Article : Google Scholar : PubMed/NCBI
11	Weidle UH, Birzele F, Kollmorgen G and Ruger R: Long non-coding RNAs and their role in metastasis. Cancer Genomics Proteomics. 14:143–160. 2017. View Article : Google Scholar : PubMed/NCBI
12	Wu L, Pan C, Wei X, Shi Y, Zheng J, Lin X and Shi L: lncRNA KRAL reverses 5-fluorouracil resistance in hepatocellular carcinoma cells by acting as a ceRNA against miR-141. Cell Commun Signal. 16:472018. View Article : Google Scholar : PubMed/NCBI
13	Huang H, Chen J, Ding CM, Jin X, Jia ZM and Peng J: LncRNA NR2F1-AS1 regulates hepatocellular carcinoma oxaliplatin resistance by targeting ABCC1 via miR-363. J Cell Mol Med. 22:3238–3245. 2018. View Article : Google Scholar : PubMed/NCBI
14	Xiao J, Lv Y, Jin F, Liu Y, Ma Y, Xiong Y, Liu L, Zhang S, Sun Y, Tipoe GL, et al: LncRNA HANR promotes tumorigenesis and increase of chemoresistance in hepatocellular carcinoma. Cell Physiol Biochem. 43:1926–1938. 2017. View Article : Google Scholar : PubMed/NCBI
15	Li Y, Ye Y, Feng B and Qi Y: Long noncoding RNA lncARSR promotes doxorubicin resistance in hepatocellular carcinoma via modulating PTEN-PI3K/Akt pathway. J Cell Biochem. 118:4498–4507. 2017. View Article : Google Scholar : PubMed/NCBI
16	Loewer S, Cabili MN, Guttman M, Loh YH, Thomas K, Park IH, Garber M, Curran M, Onder T, Agarwal S, et al: Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nat Genet. 42:1113–1117. 2010. View Article : Google Scholar : PubMed/NCBI
17	Wang Y, Xu Z, Jiang J, Xu C, Kang J, Xiao L, Wu M, Xiong J, Guo X and Liu H: Endogenous miRNA sponge lincRNA-RoR regulates Oct4, Nanog, and Sox2 in human embryonic stem cell self-renewal. Dev Cell. 25:69–80. 2013. View Article : Google Scholar : PubMed/NCBI
18	Hou P, Zhao Y, Li Z, Yao R, Ma M, Gao Y, Zhao L, Zhang Y, Huang B and Lu J: LincRNA-ROR induces epithelial-to-mesenchymal transition and contributes to breast cancer tumorigenesis and metastasis. Cell Death Dis. 5:e12872014. View Article : Google Scholar : PubMed/NCBI
19	Zhou X, Gao Q, Wang J, Zhang X, Liu K and Duan Z: Linc-RNA-RoR acts as a ‘sponge’ against mediation of the differentiation of endometrial cancer stem cells by microRNA-145. Gynecol Oncol. 133:333–339. 2014. View Article : Google Scholar : PubMed/NCBI
20	Gao S, Wang P, Hua Y, Xi H, Meng Z, Liu T, Chen Z and Liu L: ROR functions as a ceRNA to regulate Nanog expression by sponging miR-145 and predicts poor prognosis in pancreatic cancer. Oncotarget. 7:1608–1618. 2016. View Article : Google Scholar : PubMed/NCBI
21	Wang S, Liu F, Deng J, Cai X, Han J and Liu Q: Long noncoding RNA ROR regulates proliferation, invasion, and stemness of gastric cancer stem cell. Cell Reprogram. 18:319–326. 2016. View Article : Google Scholar : PubMed/NCBI
22	Li C, Lu L, Feng B, Zhang K, Han S, Hou D, Chen L, Chu X and Wang R: The lincRNA-ROR/miR-145 axis promotes invasion and metastasis in hepatocellular carcinoma via induction of epithelial-mesenchymal transition by targeting ZEB2. Sci Rep. 7:46372017. View Article : Google Scholar : PubMed/NCBI
23	Takahashi K, Yan IK, Haga H and Patel T: Modulation of hypoxia-signaling pathways by extracellular linc-RoR. J Cell Sci. 127:1585–1594. 2014. View Article : Google Scholar : PubMed/NCBI
24	Takahashi K, Yan IK, Kogure T, Haga H and Patel T: Extracellular vesicle-mediated transfer of long non-coding RNA ROR modulates chemosensitivity in human hepatocellular cancer. FEBS Open Bio. 4:458–467. 2014. View Article : Google Scholar : PubMed/NCBI
25	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
26	Odero-Marah V, Hawsawi O, Henderson V and Sweeney J: Epithelial-mesenchymal transition (EMT) and prostate cancer. Adv Exp Med Biol. 1095:101–110. 2018. View Article : Google Scholar : PubMed/NCBI
27	Yee NS: Update in systemic and targeted therapies in gastrointestinal oncology. Biomedicines. 6:342018. View Article : Google Scholar
28	Kudo M: Systemic therapy for hepatocellular carcinoma: 2017 update. Oncology. 93 (Suppl 1):S135–S146. 2017. View Article : Google Scholar
29	Nishida N, Kitano M, Sakurai T and Kudo M: Molecular mechanism and prediction of sorafenib chemoresistance in human hepatocellular carcinoma. Dig Dis. 33:771–779. 2015. View Article : Google Scholar : PubMed/NCBI
30	Lohitesh K, Chowdhury R and Mukherjee S: Resistance a major hindrance to chemotherapy in hepatocellular carcinoma: An insight. Cancer Cell Int. 18:442018. View Article : Google Scholar : PubMed/NCBI
31	Li C, Chen J, Zhang K, Feng B, Wang R and Chen L: Progress and prospects of long noncoding RNAs (lncRNAs) in hepatocellular carcinoma. Cell Physiol Biochem. 36:423–434. 2015. View Article : Google Scholar : PubMed/NCBI
32	Li CH and Chen Y: Targeting long non-coding RNAs in cancers: Progress and prospects. Int J Biochem Cell Biol. 45:1895–1910. 2013. View Article : Google Scholar : PubMed/NCBI
33	Chen Y, Shen Z, Zhi Y, Zhou H, Zhang K, Wang T, Feng B, Chen Y, Song H, Wang R and Chu X: Long non-coding RNA ROR promotes radioresistance in hepatocelluar carcinoma cells by acting as a ceRNA for microRNA-145 to regulate RAD18 expression. Arch Biochem Biophys. 645:117–125. 2018. View Article : Google Scholar : PubMed/NCBI
34	Pan Y, Li C, Chen J, Zhang K, Chu X, Wang R and Chen L: The emerging roles of long noncoding RNA ROR (lincRNA-ROR) and its possible mechanisms in human cancers. Cell Physiol Biochem. 40:219–229. 2016. View Article : Google Scholar : PubMed/NCBI
35	Lou Y, Jiang H, Cui Z, Wang L, Wang X and Tian T: Linc-ROR induces epithelial-to-mesenchymal transition in ovarian cancer by increasing Wnt/β-catenin signaling. Oncotarget. 8:69983–69994. 2017. View Article : Google Scholar : PubMed/NCBI
36	Pan Y, Chen J, Tao L, Zhang K, Wang R, Chu X and Chen L: Long noncoding RNA ROR regulates chemoresistance in docetaxel-resistant lung adenocarcinoma cells via epithelial mesenchymal transition pathway. Oncotarget. 8:33144–33158. 2017. View Article : Google Scholar : PubMed/NCBI
37	Sahebi R, Malakootian M, Balalaee B, Shahryari A, Khoshnia M, Abbaszadegan MR, Moradi A and Javad Mowla S: Linc-ROR and its spliced variants 2 and 4 are significantly up-regulated in esophageal squamous cell carcinoma. Iran J Basic Med Sci. 19:1131–1135. 2016.PubMed/NCBI
38	Shi J, Zhang W, Tian H, Zhang Q and Men T: lncRNA ROR promotes the proliferation of renal cancer and is negatively associated with favorable prognosis. Mol Med Rep. 16:9561–9566. 2017. View Article : Google Scholar : PubMed/NCBI
39	Chaffer CL, San Juan BP, Lim E and Weinberg RA: EMT, cell plasticity and metastasis. Cancer Metastasis Rev. 35:645–654. 2016. View Article : Google Scholar : PubMed/NCBI
40	Zheng HC: The molecular mechanisms of chemoresistance in cancers. Oncotarget. 8:59950–59964. 2017. View Article : Google Scholar : PubMed/NCBI
41	Kang Y and Massagué J: Epithelial-mesenchymal transitions: Twist in development and metastasis. Cell. 118:277–279. 2004. View Article : Google Scholar : PubMed/NCBI
42	Wang Y, Sun B, Zhao X, Zhao N, Sun R, Zhu D, Zhang Y, Li Y, Gu Q, Dong X, et al: Twist1-related miR-26b-5p suppresses epithelial-mesenchymal transition, migration and invasion by targeting SMAD1 in hepatocellular carcinoma. Oncotarget. 7:24383–24401. 2016. View Article : Google Scholar : PubMed/NCBI
43	Wang D, Han S, Wang X, Peng R and Li X: SOX5 promotes epithelial-mesenchymal transition and cell invasion via regulation of Twist1 in hepatocellular carcinoma. Med Oncol. 32:4612015.PubMed/NCBI
44	Liu YR, Liang L, Zhao JM, Zhang Y, Zhang M, Zhong WL, Zhang Q, Wei JJ, Li M, Yuan J, et al: Twist1 confers multidrug resistance in colon cancer through upregulation of ATP-binding cassette transporters. Oncotarget. 8:52901–52912. 2017. View Article : Google Scholar : PubMed/NCBI
45	Ávila-Moreno F, Armas-López L, Álvarez-Moran AM, López-Bujanda Z, Ortiz-Quintero B, Hidalgo-Miranda A, Urrea-Ramírez F, Rivera-Rosales RM, Vázquez-Manríquez E, Peña-Mirabal E, et al: Overexpression of MEOX2 and TWIST1 is associated with H3K27me3 levels and determines lung cancer chemoresistance and prognosis. PLoS One. 9:e1141042014. View Article : Google Scholar : PubMed/NCBI
46	Wang R, Li Y, Hou Y, Yang Q, Chen S, Wang X, Wang Z, Yang Y, Chen C, Wang Z and Wu Q: The PDGF-D/miR-106a/Twist1 pathway orchestrates epithelial-mesenchymal transition in gemcitabine resistance hepatoma cells. Oncotarget. 6:7000–7010. 2015. View Article : Google Scholar : PubMed/NCBI
47	Xue F, Liu Y, Chu H, Wen Y, Yan L, Tang Q, Xiao E, Zhang D and Zhang H: eIF5A2 is an alternative pathway for cell proliferation in cetuximab-treated epithelial hepatocellular carcinoma. Am J Transl Res. 8:4670–4681. 2016.PubMed/NCBI