Long non‑coding RNA GAS5 is critical for maintaining stemness and induces chemoresistance in cancer stem‑like cells derived from HCT116

Zhou,Xiong; Xiao,Dachun

doi:10.3892/ol.2020.11471

Long non‑coding RNA GAS5 is critical for maintaining stemness and induces chemoresistance in cancer stem‑like cells derived from HCT116

Authors:
- Xiong Zhou
- Dachun Xiao
View Affiliations

Affiliations: Department of Gastrointestinal Surgery, Yongchuan Hospital of Chongqing Medical University, Chongqing 410000, P.R. China
Published online on: March 20, 2020 https://doi.org/10.3892/ol.2020.11471
Pages: 3431-3438
Copyright: © Zhou 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 (lncRNAs) are recognized as critical regulators of self-renewal in human cancer stem-like cells (CSCs), which are a subpopulation of cancer cells primarily responsible for the malignant features of cancer. However, most CSC‑related lncRNAs remain unidentified. The results of the present study suggested that growth‑arrest‑specific transcript 5 (GAS5), a tumor suppressor, exhibited increased expression and was associated with malignant features in human colorectal cancer cell HCT116‑derived CSCs. Phenotypic analysis indicated that GAS5 knockdown by specific siRNA significantly decreased CSC self‑renewal capacity, proliferation and migration. Moreover, GAS5 knockdown sensitized CSCs to the chemotherapeutic agents 5‑fluorouracil and doxorubicin by inducing apoptosis detected by Annexin V‑FITC/PI double staining. Inhibition of Nodal growth differentiation factor (NODAL) signaling, which has been reported to be protected by GAS5, presented similar chemosensitivity effects to the GAS5 knockdown results. The present study also assessed the effects of GAS5 overexpression on HCT116 cells, and revealed that overexpression of GAS5 sensitized HCT116 cells to chemotherapeutic agents, which is the opposite of the effect observed in CSCs derived from HCT116 cells. Therefore, it was hypothesized that GAS5 may function as a critical factor for maintaining stemness and that it may exert protective effects on CSCs in a NODAL‑dependent manner. Collectively, the results of the present study indicate that GAS5 may be a promising therapeutic target for overcoming malignant features and chemoresistance in colorectal cancer cells.

View Figures

View References

1	Marmol I, Sanchez-de-Diego C, Pradilla DA, Cerrada E and Rodriguez YM: Colorectal carcinoma: A general overview and future perspectives in colorectal cancer. Int J Mol Sci. 18:E1972017. View Article : Google Scholar : PubMed/NCBI
2	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
3	Papanastasopoulos P and Stebbing J: Molecular basis of 5-fluorouracil-related toxicity: Lessons from clinical practice. Anticancer Res. 34:1531–1535. 2014.PubMed/NCBI
4	Bharti AC and Aggarwal BB: Nuclear factor-kappa B and cancer: Its role in prevention and therapy. Biochem Pharmacol. 64:883–888. 2002. View Article : Google Scholar : PubMed/NCBI
5	Huang J, Chen Y, Li J, Zhang K, Chen J, Chen D, Feng B, Song H, Feng J, Wang R and Chen L: Notch-1 confers chemoresistance in lung adenocarcinoma to Taxanes through AP-1/microRNA-451 mediated regulation of MDR-1. Mol Ther Nucleic Acids. 5:e3752016. View Article : Google Scholar : PubMed/NCBI
6	Xie Y and Zhong DW: AEG-1 is associated with hypoxia-induced hepatocellular carcinoma chemoresistance via regulating PI3K/AKT/HIF-1alpha/MDR-1 pathway. EXCLI J. 15:745–757. 2016.PubMed/NCBI
7	Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C and De Maria R: Identification and expansion of human colon-cancer-initiating cells. Nature. 445:111–115. 2007. View Article : Google Scholar : PubMed/NCBI
8	Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, Hoey T, Gurney A, Huang EH, Simeone DM, et al: Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA. 104:10158–10163. 2007. View Article : Google Scholar : PubMed/NCBI
9	Magee JA, Piskounova E and Morrison SJ: Cancer stem cells: Impact, heterogeneity, and uncertainty. Cancer Cell. 21:283–296. 2012. View Article : Google Scholar : PubMed/NCBI
10	Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL and Wahl GM: Cancer stem cells-perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 66:9339–9344. 2006. View Article : Google Scholar : PubMed/NCBI
11	Reya T, Morrison SJ, Clarke MF and Weissman IL: Stem cells, cancer, and cancer stem cells. Nature. 414:105–111. 2001. View Article : Google Scholar : PubMed/NCBI
12	Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD and Dirks PB: Identification of human brain tumour initiating cells. Nature. 432:396–401. 2004. View Article : Google Scholar : PubMed/NCBI
13	Vander Griend DJ, Karthaus WL, Dalrymple S, Meeker A, DeMarzo AM and Isaacs JT: The role of CD133 in normal human prostate stem cells and malignant cancer-initiating cells. Cancer Res. 68:9703–9711. 2008. View Article : Google Scholar : PubMed/NCBI
14	Seymour T, Nowak A and Kakulas F: Targeting aggressive cancer stem cells in glioblastoma. Front Oncol. 5:1592015. View Article : Google Scholar : PubMed/NCBI
15	Watanabe Y, Yoshimura K, Yoshikawa K, Tsunedomi R, Shindo Y, Matsukuma S, Maeda N, Kanekiyo S, Suzuki N, Kuramasu A, et al: A stem cell medium containing neural stimulating factor induces a pancreatic cancer stem-like cell-enriched population. Int J Oncol. 45:1857–1866. 2014. View Article : Google Scholar : PubMed/NCBI
16	Matsukuma S, Yoshimura K, Ueno T, Oga A, Inoue M, Watanabe Y, Kuramasu A, Fuse M, Tsunedomi R, Nagaoka S, et al: Calreticulin is highly expressed in pancreatic cancer stem-like cells. Cancer Sci. 107:1599–1609. 2016. View Article : Google Scholar : PubMed/NCBI
17	Hashimoto N, Tsunedomi R, Yoshimura K, Watanabe Y, Hazama S and Oka M: Cancer stem-like sphere cells induced from de-differentiated hepatocellular carcinoma-derived cell lines possess the resistance to anti-cancer drugs. BMC Cancer. 14:7222014. View Article : Google Scholar : PubMed/NCBI
18	Wang F, Ma L, Zhang Z, Liu X, Gao H, Zhuang Y, Yang P, Kornmann M, Tian X and Yang Y: Hedgehog signaling regulates epithelial-mesenchymal transition in pancreatic cancer stem-like cells. J Cancer. 7:408–417. 2016. View Article : Google Scholar : PubMed/NCBI
19	Nakamura Y, Takahashi N, Kakegawa E, Yoshida K, Ito Y, Kayano H, Niitsu N, Jinnai I and Bessho M: The GAS5 (growth arrest-specific transcript 5) gene fuses to BCL6 as a result of t(1;3)(q25;q27) in a patient with B-cell lymphoma. Cancer Genet Cytogenet. 182:144–149. 2008. View Article : Google Scholar : PubMed/NCBI
20	Ye K, Wang S, Zhang H, Han H, Ma B and Nan W: Long noncoding RNA GAS5 suppresses cell growth and epithelial-mesenchymal transition in osteosarcoma by regulating the miR-221/ARHI pathway. J Cell Biochem. 118:4772–4781. 2017. View Article : Google Scholar : PubMed/NCBI
21	Wen Q, Liu Y, Lyu H, Xu X, Wu Q, Liu N, Yin Q, Li J and Sheng X: Long Noncoding RNA GAS5, which acts as a tumor suppressor via microRNA 21, regulates cisplatin resistance expression in cervical cancer. Int J Gynecol Cancer. 27:1096–1108. 2017. View Article : Google Scholar : PubMed/NCBI
22	Liu B, Wu S, Ma J, Yan S, Xiao Z, Wan L, Zhang F, Shang M and Mao A: lncRNA GAS5 reverses EMT and tumor stem cell-mediated gemcitabine resistance and metastasis by targeting miR-221/SOCS3 in pancreatic cancer. Mol Ther Nucleic Acids. 13:472–482. 2018. View Article : Google Scholar : PubMed/NCBI
23	Dong X, Kong C, Liu X, Bi J, Li Z, Li Z, Zhu Y and Zhang Z: GAS5 functions as a ceRNA to regulate hZIP1 expression by sponging miR-223 in clear cell renal cell carcinoma. Am J Cancer Res. 8:1414–1426. 2018.PubMed/NCBI
24	Zhao J, Fu Y, Wu J, Li J, Huang G and Qin L: The diverse mechanisms of miRNAs and lncRNAs in the maintenance of liver cancer stem cells. Biomed Res Int. 2018:86860272018. View Article : Google Scholar : PubMed/NCBI
25	Wang L, Dong P, Wang W, Huang M and Tian B: Gemcitabine treatment causes resistance and malignancy of pancreatic cancer stem-like cells via induction of lncRNA HOTAIR. Exp Ther Med. 14:4773–4780. 2017.PubMed/NCBI
26	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
27	Noh KH, Kim BW, Song KH, Cho H, Lee YH, Kim JH, Chung JY, Kim JH, Hewitt SM, Seong SY, et al: Nanog signaling in cancer promotes stem-like phenotype and immune evasion. J Clin Invest. 122:4077–4093. 2012. View Article : Google Scholar : PubMed/NCBI
28	Gkountela S and Aceto N: Stem-like features of cancer cells on their way to metastasis. Biol Direct. 11:332016. View Article : Google Scholar : PubMed/NCBI
29	Singh S, Trevino J, Bora-Singhal N, Coppola D, Haura E, Altiok S and Chellappan SP: EGFR/Src/Akt signaling modulates Sox2 expression and self-renewal of stem-like side-population cells in non-small cell lung cancer. Mol Cancer. 11:732012. View Article : Google Scholar : PubMed/NCBI
30	Xu C, Zhang Y, Wang Q, Xu Z, Jiang J, Gao Y, Gao M, Kang J, Wu M, Xiong J, et al: Long non-coding RNA GAS5 controls human embryonic stem cell self-renewal by maintaining NODAL signalling. Nat Commun. 7:132872016. View Article : Google Scholar : PubMed/NCBI
31	Long X, Song K, Hu H, Tian Q, Wang W, Dong Q, Yin X and Di W: Long non-coding RNA GAS5 inhibits DDP-resistance and tumor progression of epithelial ovarian cancer via GAS5-E2F4-PARP1-MAPK axis. J Exp Clin Cancer Res. 38:3452019. View Article : Google Scholar : PubMed/NCBI
32	Lu LL, Chen XH, Zhang G, Liu ZC, Wu N, Wang H, Qi YF, Wang HS, Cai SH and Du J: CCL21 facilitates chemoresistance and cancer stem cell-like Properties of colorectal cancer cells through AKT/GSK-3β/Snail signals. Oxid Med Cell Longev. 2016:58741272016. View Article : Google Scholar : PubMed/NCBI
33	Cioffi M, Trabulo SM, Sanchez-Ripoll Y, Miranda-Lorenzo I, Lonardo E, Dorado J, Reis Vieira C, Ramirez JC, Hidalgo M, Aicher A, et al: The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells. Gut. 64:1936–1948. 2015. View Article : Google Scholar : PubMed/NCBI