Exosomal lncRNA UCA1 from cancer-associated fibroblasts enhances chemoresistance in vulvar squamous cell carcinoma cells.

Publisher: Wiley on behalf of the Japan Society of Obstetrics and Gynecology] Country of Publication: Australia NLM ID: 9612761 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1447-0756 (Electronic) Linking ISSN: 13418076 NLM ISO Abbreviation: J Obstet Gynaecol Res Subsets: MEDLINE

Publication: [Melbourne, Vic. : Wiley on behalf of the Japan Society of Obstetrics and Gynecology]
Original Publication: Tokyo : University of Tokyo Press, c1996-

Cancer-Associated Fibroblasts* ; Carcinoma, Squamous Cell* ; MicroRNAs*/genetics ; RNA, Long Noncoding*/genetics; Animals ; Cell Line, Tumor ; Cell Proliferation ; Drug Resistance, Neoplasm ; Female ; Humans ; Mice

Aim: In the current work, we aimed to explore whether Cancer-associated fibroblasts (CAF) exosomes played crucial roles in vulvar squamous cell carcinoma (VSCC) chemoresistance via mediating long noncoding RNAs (lncRNA).
Methods: The IC50 value and cell apoptosis were assessed by the Cell Counting-8 Kit (CCK-8) assay and flow cytometry, respectively. Western blot analysis was used for the measurement of protein levels. The levels of urothelial cancer-associated 1 (UCA1), miR-103a and WEE1 G2 checkpoint kinase (WEE1) mRNA were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The target relationships among miR-103a, UCA1 and WEE1 were confirmed by dual-luciferase reporter assays. Xenograft model mice were established to observe the impact of exosomal UCA1 on cisplatin (CDDP) resistance in vivo.
Results: Our data indicated that CAF enhanced CDDP resistance of VSCC cells in vitro. Extracellular UCA1 was transferred by exosomes derived from CAF. Exosomal UCA1 derived from CAF conferred VSCC cell resistance to CDDP. Moreover, UCA1 functioned as a miR-103a sponge in VSCC cells. The promotion of exosomal UCA1 on VSCC cell resistance to CDDP was mediated by miR-103a. WEE1 was a direct target of miR-103a, and exosomal miR-103a from CAF weakened CDDP resistance of VSCC cells by WEE1. Furthermore, exosomal UCA1 regulated WEE1 expression through sponging miR-103a. Additionally, exosomal UCA1 enhanced tumor growth and CDDP resistance in vivo.
Conclusion: Our findings suggested exosomal UCA1 derived from CAF conferred VSCC cell resistance to CDDP in vitro and in vivo at least partly through the miR-103a/WEE1 axis, highlighting a novel therapeutic method for improving the clinical benefits of CDDP chemotherapy in VSCC patients.
(© 2020 Japan Society of Obstetrics and Gynecology.)

Allbritton JI. Vulvar neoplasms, benign and malignant. Obstet Gynecol Clin N Am 2017; 44: 339-352.
Clancy AA, Spaans JN, Weberpals JI. The forgotten womans cancer, vulvar squamous cell carcinoma (VSCC) and a targeted approach to therapy. Ann Oncol 2016; 27: 1696-1705.
Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. J Cell Sci 2012; 125: 5591-5596.
Augsten M. Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front Oncol 2014; 4: 62.
Huelsken J, Hanahan D. A subset of cancer-associated fibroblasts determines therapy resistance. Cell 2018; 172: 643-644.
Leung CS, Yeung TL, Yip KP et al. Cancer-associated fibroblasts regulate endothelial adhesion protein LPP to promote ovarian cancer chemoresistance. J Clin Invest 2018; 128: 589-606.
Su S, Chen J, Yao H et al. CD10(+)GPR77(+) cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell 2018; 172: 841-856 e816.
Couto N, Caja S, Maia J, Strano Moraes MC, Costa-Silva B. Exosomes as emerging players in cancer biology. Biochimie 2018; 155: 2-10.
Couzin J. Cell biology, the ins and outs of exosomes. Science 2005; 308: 1862-1863.
Mashouri L, Yousefi H, Aref AR, Ahadi AM, Molaei F, Alahari SK. Exosomes, composition, biogenesis, and mechanisms in cancer metastasis and drug resistance. Mol Cancer 2019; 18: 75.
Li I, Nabet BY. Exosomes in the tumor microenvironment as mediators of cancer therapy resistance. Mol Cancer 2019; 18: 32.
Lobb RJ, van Amerongen R, Wiegmans A, Ham S, Larsen JE, Moller A. Exosomes derived from mesenchymal non-small cell lung cancer cells promote chemoresistance. Int J Cancer 2017; 141: 614-620.
Zeng AL, Yan W, Liu YW et al. Tumour exosomes from cells harbouring PTPRZ1-MET fusion contribute to a malignant phenotype and temozolomide chemoresistance in glioblastoma. Oncogene 2017; 36: 5369-5381.
Ni S, Zhao X, Ouyang L. Long non-coding RNA expression profile in vulvar squamous cell carcinoma and its clinical significance. Oncol Rep 2016; 36: 2571-2578.
Wang H, Ouyang L, Gao S. Effects of antisense lncRNA PCBP1-AS1 on biological behaviors of vulvar squamous carcinoma cells by regulating TRAF5 and NF-κB expression. Transl Cancer Res 2019; 8: 1578-1590.
Fang Z, Zhao J, Xie W, Sun Q, Wang H, Qiao B. LncRNA UCA1 promotes proliferation and cisplatin resistance of oral squamous cell carcinoma by sunppressing miR-184 expression. Cancer Med 2017; 6: 2897-2908.
Sun S, Gong C, Yuan K. LncRNA UCA1 promotes cell proliferation, invasion and migration of laryngeal squamous cell carcinoma cells by activating Wnt/beta-catenin signaling pathway. Exp Ther Med 2019; 17: 1182-1189.
Pan J, Li X, Wu W et al. Long non-coding RNA UCA1 promotes cisplatin/gemcitabine resistance through CREB modulating miR-196a-5p in bladder cancer cells. Cancer Lett 2016; 382: 64-76.
Xue M, Chen W, Xiang A et al. Hypoxic exosomes facilitate bladder tumor growth and development through transferring long non-coding RNA-UCA1. Mol Cancer 2017; 16: 143.
Xu CG, Yang MF, Ren YQ, Wu CH, Wang LQ. Exosomes mediated transfer of lncRNA UCA1 results in increased tamoxifen resistance in breast cancer cells. Eur Rev Med Pharmacol Sci 2016; 20: 4362-4368.
Yang YN, Zhang R, Du JW et al. Predictive role of UCA1-containing exosomes in cetuximab-resistant colorectal cancer. Cancer Cell Int 2018; 18: 164.
Sanchez-Mejias A, Tay Y. Competing endogenous RNA networks, tying the essential knots for cancer biology and therapeutics. J Hematol Oncol 2015; 8: 30.
Fan Z, Yang J, Zhang D et al. The risk variant rs884225 within EGFR impairs miR-103a-3p's anti-tumourigenic function in non-small cell lung cancer. Oncogene 2019; 38: 2291-2304.
Yu M, Xue Y, Zheng J et al. Linc00152 promotes malignant progression of glioma stem cells by regulating miR-103a-3p/FEZF1/CDC25A pathway. Mol Cancer 2017; 16: 110.
Yang X, Wu X. miRNA expression profile of vulvar squamous cell carcinoma and identification of the oncogenic role of miR-590-5p. Oncol Rep 2016; 35: 398-408.
Shintani Y, Fujiwara A, Kimura T et al. IL-6 secreted from cancer-associated fibroblasts mediates chemoresistance in NSCLC by increasing epithelial-mesenchymal transition signaling. J Thorac Oncol 2016; 11: 1482-1492.
Shi J, Wang H, Feng W et al. Long non-coding RNA HOTTIP promotes hypoxia-induced glycolysis through targeting miR-615-3p/HMGB3 axis in non-small cell lung cancer cells. Eur J Pharmacol 2019; 862: 172615.
Zhang W, Cai X, Yu J, Lu X, Qian Q, Qian W. Exosome-mediated transfer of lncRNA RP11-838N2. 4 promotes erlotinib resistance in non-small cell lung cancer. Int J Oncol 2018; 53: 527-538.
Himbert D, Junker K, Stöckle M. Characterization of tumor-associated exosomes secreted by renal cell carcinoma cell lines. Eur Urol Suppl 2018; 17: e2560.
Liu C, Pan C, Cai Y, Wang H. Interplay between long noncoding RNA ZEB1-AS1 and miR-200s regulates osteosarcoma cell proliferation and migration. J Cell Biochem 2017; 118: 2250-2260.
Richards KE, Zeleniak AE, Fishel ML, Wu J, Littlepage LE, Hill R. Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene 2017; 36: 1770-1778.
Dragomir M, Chen B, Calin GA. Exosomal lncRNAs as new players in cell-to-cell communication. Transl Cancer Res 2018; 7: S243-s252.
Anastasiadou E, Jacob LS, Slack FJ. Non-coding RNA networks in cancer. Nat Rev Cancer 2018; 18: 5-18.
Magnussen GI, Hellesylt E, Nesland JM, Trope CG, Florenes VA, Holm R. High expression of wee1 is associated with malignancy in vulvar squamous cell carcinoma patients. BMC Cancer 2013; 13: 288.
Yuan ML, Li P, Xing ZH et al. Inhibition of WEE1 suppresses the tumor growth in laryngeal squamous cell carcinoma. Front Pharmacol 2018; 9: 1041.
Richards KE. Pancreatic cancer-associated fibroblast exosomes alter pancreatic cancer cell chemoresistance (Dissertation). University Of Notre Dame, 2018.
Santos JC, Ribeiro ML, Sarian LO, Ortega MM, Derchain SF. Exosomes-mediate microRNAs transfer in breast cancer chemoresistance regulation. Am J Cancer Res 2016; 6: 2129-2139.
Ren J, Ding L, Zhang D et al. Carcinoma-associated fibroblasts promote the stemness and chemoresistance of colorectal cancer by transferring exosomal lncRNA H19. Theranostics 2018; 8: 3932-3948.
Robey RW, Pluchino KM, Hall MD, Fojo AT, Bates SE, Gottesman MM. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat Rev Cancer 2018; 18: 452-464.
Michels J, Obrist F, Vitale I et al. MCL-1 dependency of cisplatin-resistant cancer cells. Biochem Pharmacol 2014; 92: 55-61.
Barth S, Glick D, Macleod KF. Autophagy, assays and artifacts. J Pathol 2010; 221: 117-124.
Deng X, Ruan H, Zhang X et al. Long noncoding RNA CCAL transferred from fibroblasts by exosomes promotes chemoresistance of colorectal cancer cells. Int J Cancer 2020; 146 (6): 1700-1716.
Liang J, Liu X, Xue H, Qiu B, Wei B, Sun K. MicroRNA-103a inhibits gastric cancer cell proliferation, migration and invasion by targeting c-Myb. Cell Prolif 2015; 48: 78-85.
Zhong Z, Lv M, Chen J. Screening differential circular RNA expression profiles reveals the regulatory role of circTCF25-miR-103a-3p/miR-107-CDK6 pathway in bladder carcinoma. Sci Rep 2016; 6: 30919.
Fang Y, Zhou W, Rong Y et al. Exosomal miRNA-106b from cancer-associated fibroblast promotes gemcitabine resistance in pancreatic cancer. Exp Cell Res 2019; 383: 111543-111549.
Qin X, Guo H, Wang X et al. Exosomal miR-196a derived from cancer-associated fibroblasts confers cisplatin resistance in head and neck cancer through targeting CDKN1B and ING5. Genome Biol 2019; 20: 12.
Ge XC, Wu F, Li WT, Zhu XJ, Liu JW, Wang BL. Upregulation of WEE1 is a potential prognostic biomarker for patients with colorectal cancer. Oncol Lett 2017; 13: 4341-4348.
Kim HY, Cho Y, Kang H et al. Targeting the WEE1 kinase as a molecular targeted therapy for gastric cancer. Oncotarget 2016; 7: 49902-49916.
Geenen JJJ, Schellens JHM. Molecular pathways, targeting the protein kinase Wee1 in cancer. Clin Cancer Res 2017; 23: 4540-4544.

Keywords: cancer-associated fibroblast; chemoresistance; exosome; urothelial cancer-associated 1; vulvar squamous cell carcinoma

0 (MicroRNAs)
0 (RNA, Long Noncoding)
0 (UCA1 RNA, human)

Date Created: 20200820 Date Completed: 20210621 Latest Revision: 20220531

20231215

10.1111/jog.14418

32812305