Flotillin‑2 predicts poor prognosis and promotes tumor invasion in intrahepatic cholangiocarcinoma

Xu,Zhiying; Wang,Tao; Song,Haiyang; Jiang,Xuewen

doi:10.3892/ol.2020.11349

Flotillin‑2 predicts poor prognosis and promotes tumor invasion in intrahepatic cholangiocarcinoma

Authors:
- Zhiying Xu
- Tao Wang
- Haiyang Song
- Xuewen Jiang
View Affiliations

Affiliations: Department of Nuclear Medicine, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264001, P.R. China, Department of Interventional Therapy, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264001, P.R. China
Published online on: January 24, 2020 https://doi.org/10.3892/ol.2020.11349
Pages: 2243-2250
Copyright: © Xu 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

Intrahepatic cholangiocarcinoma (iCCA) is a highly malignant neoplasm arising from the intrahepatic bile ducts. As a scaffold protein of lipid rafts, flotillin‑2 is upregulated in several types of cancer and promotes tumor progression and metastasis. To the best of our knowledge, the present study was the first to detect the upregulation of flotillin‑2 in iCCA tissues compared with matched adjacent non‑tumor tissues. In addition, immunohistochemistry was used to investigate the expression of flotillin‑2 in a microarray consisting of 92 iCCA tissues. A total of 59 samples (64.1%) exhibited high flotillin‑2 expression, which was significantly related to lymph node metastasis (P=0.029) and tumor‑node‑metastasis stage (P=0.016). Further in vitro study demonstrated that knockdown of flotillin‑2 inhibited the invasive capability of iCCA cell lines, further supporting the participation of flotillin‑2 in cancer invasion and metastasis. Moreover, Kaplan‑Meier analysis showed patients with high flotillin‑2 expression had worse overall survival outcomes. The multivariate Cox proportional hazards model further revealed that high flotillin‑2 expression was an independent indicator (P=0.005) of poor prognosis for patients with iCCA. Collectively, the present study revealed that as a promoter of invasion and an independent marker of poor prognosis, flotillin‑2 may serve as a potential target for the development of novel therapeutic agents for iCCA.

View Figures

View References

1	Maithel SK, Gamblin TC, Kamel I, Corona-Villalobos CP, Thomas M and Pawlik TM: Multidisciplinary approaches to intrahepatic cholangiocarcinoma. Cancer. 119:3929–3942. 2013. View Article : Google Scholar : PubMed/NCBI
2	Tao R, Krishnan S, Bhosale PR, Javle MM, Aloia TA, Shroff RT, Kaseb AO, Bishop AJ, Swanick CW, Koay EJ, et al: Ablative radiotherapy doses lead to a substantial prolongation of survival in patients with inoperable intrahepatic cholangiocarcinoma: A retrospective dose response analysis. J Clin Oncol. 34:219–226. 2016. View Article : Google Scholar : PubMed/NCBI
3	Chan KM, Tsai CY, Yeh CN, Yeh TS, Lee WC, Jan YY and Chen MF: Characterization of intrahepatic cholangiocarcinoma after curative resection: Outcome, prognostic factor, and recurrence. BMC Gastroenterol. 18:1802018. View Article : Google Scholar : PubMed/NCBI
4	Moeini A, Sia D, Bardeesy N, Mazzaferro V and Llovet JM: Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma. Clin Cancer Res. 22:291–300. 2016. View Article : Google Scholar : PubMed/NCBI
5	Rivera-Milla E, Stuermer CA and Malaga-Trillo E: Ancient origin of reggie (flotillin), reggie-like, and other lipid-raft proteins: Convergent evolution of the SPFH domain. Cell Mol Life Sci. 63:343–357. 2006. View Article : Google Scholar : PubMed/NCBI
6	Planchon D, Rios Morris E, Genest M, Comunale F, Vacher S, Bièche I, Denisov EV, Tashireva LA, Perelmuter VM, Linder S, et al: MT1-MMP targeting to endolysosomes is mediated by upregulation of flotillins. J Cell Sci. 131:jcs2189252018. View Article : Google Scholar : PubMed/NCBI
7	Banning A, Babuke T, Kurrle N, Meister M, Ruonala MO and Tikkanen R: Flotillins regulate focal adhesions by interacting with α-actinin and by influencing the activation of focal adhesion kinase. Cells. 7:E282018. View Article : Google Scholar : PubMed/NCBI
8	Dong Z, Cheng F, Yang Y, Zhang F, Chen G and Liu D: Expression and functional analysis of flotillins in Dugesia japonica. Exp Cell Res. 374:76–84. 2019. View Article : Google Scholar : PubMed/NCBI
9	Head BP, Patel HH and Insel PA: Interaction of membrane/lipid rafts with the cytoskeleton: Impact on signaling and function: Membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling. Biochim Biophys Acta. 1838:532–545. 2014. View Article : Google Scholar : PubMed/NCBI
10	Stuermer CA: How reggies regulate regeneration and axon growth. Cell Tissue Res. 349:71–77. 2012. View Article : Google Scholar : PubMed/NCBI
11	Zhao F, Zhang J, Liu YS, Li L and He YL: Research advances on flotillins. Virol J. 8:4792011. View Article : Google Scholar : PubMed/NCBI
12	Cao K, Xie D, Cao P, Zou Q, Lu C, Xiao S, Zhou J and Peng X: SiRNA-mediated flotillin-2 (Flot2) downregulation inhibits cell proliferation, migration, and invasion in gastric carcinoma cells. Oncol Res. 21:271–279. 2014. View Article : Google Scholar : PubMed/NCBI
13	Berger T, Ueda T, Arpaia E, Chio II, Shirdel EA, Jurisica I, Hamada K, You-Ten A, Haight J, Wakeham A, et al: Flotillin-2 deficiency leads to reduced lung metastases in a mouse breast cancer model. Oncogene. 32:4989–4994. 2013. View Article : Google Scholar : PubMed/NCBI
14	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
15	Li T, Cao C, Xiong Q and Liu D: FLOT2 overexpression is associated with the progression and prognosis of human colorectal cancer. Oncol Lett. 17:2802–2808. 2019.PubMed/NCBI
16	Vega-Cabrera LA and Pardo-Lopez L: Membrane remodeling and organization: Elements common to prokaryotes and eukaryotes. IUBMB life. 69:55–62. 2017. View Article : Google Scholar : PubMed/NCBI
17	Bodin S, Planchon D, Rios Morris E, Comunale F and Gauthier-Rouviere C: Flotillins in intercellular adhesion-from cellular physiology to human diseases. J Cell Sci. 127:5139–5147. 2014. View Article : Google Scholar : PubMed/NCBI
18	Mou X and Liu S: MiR-485 inhibits metastasis and EMT of lung adenocarcinoma by targeting Flot2. Biochem Biophys Res Commun. 477:521–526. 2016. View Article : Google Scholar : PubMed/NCBI
19	Wei G, Xu Y, Peng T and Yan J: miR-133 involves in lung adenocarcinoma cell metastasis by targeting FLOT2. Artif Cells Nanomed Biotechnol. 46:224–230. 2018. View Article : Google Scholar : PubMed/NCBI
20	Huang S, Zheng S, Huang S, Cheng H, Lin Y, Wen Y and Lin W: Flot2 targeted by miR-449 acts as a prognostic biomarker in glioma. Artif Cells Nanomed Biotechnol. 47:250–255. 2019. View Article : Google Scholar : PubMed/NCBI
21	Wang D, Lu G, Shao Y and Xu D: microRNA-802 inhibits epithelial-mesenchymal transition through targeting flotillin-2 in human prostate cancer. Biosci Rep. 37:BSR201605212017. View Article : Google Scholar : PubMed/NCBI
22	Liu R, Xie H, Luo C, Chen Z, Zhou X, Xia K, Chen X, Zhou M, Cao P, Cao K and Zhou J: Identification of FLOT2 as a novel target for microRNA-34a in melanoma. J Cancer Res Clin Oncol. 141:993–1006. 2015. View Article : Google Scholar : PubMed/NCBI
23	Liu FT, Qu QG and Zhu ZM: Up-regulation of Flot-2 protein is related to lymph node metastasis and poor prognosis in human solid tumors. Minerva Chir. 72:146–156. 2017.PubMed/NCBI
24	Zhao L, Lin L, Pan C, Shi M, Liao Y, Bin J and Liao W: Flotillin-2 promotes nasopharyngeal carcinoma metastasis and is necessary for the epithelial-mesenchymal transition induced by transforming growth factor-β. Oncotarget. 6:9781–9793. 2015.PubMed/NCBI
25	Zhu Z, Wang J, Sun Z, Sun X, Wang Z and Xu H: Flotillin2 expression correlates with HER2 levels and poor prognosis in gastric cancer. PLoS One. 8:e623652013. View Article : Google Scholar : PubMed/NCBI
26	Wang X, Yang Q, Guo L, Li XH, Zhao XH, Song LB and Lin HX: Flotillin-2 is associated with breast cancer progression and poor survival outcomes. J Transl Med. 11:1902013. View Article : Google Scholar : PubMed/NCBI
27	Liu Y, Lin L, Huang Z, Ji B, Mei S, Lin Y and Shen Z: High expression of flotillin-2 is associated with poor clinical survival in cervical carcinoma. Int J Clin Exp Pathol. 8:622–628. 2015.PubMed/NCBI
28	Deng Y, Ge P, Tian T, Dai C, Wang M, Lin S, Liu K, Zheng Y, Xu P, Zhou L, et al: Prognostic value of flotillins (flotillin-1 and flotillin-2) in human cancers: A meta-analysis. Clin Chim Acta. 481:90–98. 2018. View Article : Google Scholar : PubMed/NCBI
29	Liu XX, Liu WD, Wang L, Zhu B, Shi X, Peng ZX, Zhu HC, Liu XD, Zhong MZ, Xie D, et al: Roles of flotillins in tumors. J Zhejiang Univ Sci B. 19:171–182. 2018. View Article : Google Scholar : PubMed/NCBI
30	Ye DM, Ye SC, Yu SQ, Shu FF, Xu SS, Chen QQ, Wang YL, Tang ZT and Pan C: Drug-resistance reversal in colorectal cancer cells by destruction of flotillins, the key lipid rafts proteins. Neoplasma. 66:576–583. 2019. View Article : Google Scholar : PubMed/NCBI
31	Liu J, Huang W, Ren C, Wen Q, Liu W, Yang X, Wang L, Zhu B, Zeng L, Feng X, et al: Flotillin-2 promotes metastasis of nasopharyngeal carcinoma by activating NF-κB and PI3K/Akt3 signaling pathways. Sci Rep. 5:116142015. View Article : Google Scholar : PubMed/NCBI
32	Xie G, Li J, Chen J, Tang X, Wu S and Liao C: Knockdown of flotillin-2 impairs the proliferation of breast cancer cells through modulation of Akt/FOXO signaling. Oncol Rep. 33:2285–2290. 2015. View Article : Google Scholar : PubMed/NCBI
33	Wang CH, Zhu XD, Ma DN, Sun HC, Gao DM, Zhang N, Qin CD, Zhang YY, Ye BG, Cai H, et al: Flot2 promotes tumor growth and metastasis through modulating cell cycle and inducing epithelial-mesenchymal transition of hepatocellular carcinoma. Am J Cancer Res. 7:1068–1083. 2017.PubMed/NCBI
34	Xu YF, Liu HD, Liu ZL, Pan C, Yang XQ, Ning SL, Zhang ZL, Guo S and Yu JM: Sprouty2 suppresses progression and correlates to favourable prognosis of intrahepatic cholangiocarcinoma via antagonizing FGFR2 signalling. J Cell Mol Med. 22:5596–5606. 2018. View Article : Google Scholar : PubMed/NCBI
35	Huang C, Tian Y, Peng R, Zhang C, Wang D, Han S, Jiao C, Wang X, Zhang H, Wang Y and Li X: Association of downregulation of WWOX with poor prognosis in patients with intrahepatic cholangiocarcinoma after curative resection. J Gastroenterol Hepatol. 30:421–433. 2015. View Article : Google Scholar : PubMed/NCBI
36	Yamaoka R, Ishii T, Kawai T, Yasuchika K, Miyauchi Y, Kojima H, Katayama H, Ogiso S, Fukumitsu K and Uemoto S: CD90 expression in human intrahepatic cholangiocarcinoma is associated with lymph node metastasis and poor prognosis. J Surg Oncol. 118:664–674. 2018. View Article : Google Scholar : PubMed/NCBI
37	Uchiyama K, Yamamoto M, Yamaue H, Ariizumi S, Aoki T, Kokudo N, Ebata T, Nagino M, Ohtsuka M, Miyazaki M, et al: Impact of nodal involvement on surgical outcomes of intrahepatic cholangiocarcinoma: A multicenter analysis by the Study Group for Hepatic Surgery of the Japanese Society of Hepato-Biliary-Pancreatic Surgery. J Hepatobiliary Pancreat Sci. 18:443–452. 2011. View Article : Google Scholar : PubMed/NCBI