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Molecular Cancer
Published in: Molecular Cancer 1/2017

Open Access 01-12-2017 | Research

MicroRNA-141 enhances anoikis resistance in metastatic progression of ovarian cancer through targeting KLF12/Sp1/survivin axis

Authors: Celia S. L. Mak, Mingo M. H. Yung, Lynn M. N. Hui, Leanne L. Leung, Rui Liang, Kangmei Chen, Stephanie S. Liu, Yiming Qin, Thomas H. Y. Leung, Kai-Fai Lee, Karen K. L. Chan, Hextan Y. S. Ngan, David W. Chan

Published in: Molecular Cancer | Issue 1/2017

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Abstract

Background

Cancer metastasis is determined by the formation of the metastatic niche and the ability of cancer cells to adapt to microenvironmental stresses. Anoikis resistance is a fundamental feature of metastatic cancer cell survival during metastatic cancer progression. However, the mechanisms underlying anoikis resistance in ovarian cancer are still unclear.

Methods

Expressions of miRNA-141 and its downstream targets were evaluated by qPCR, Western blotting, Immunohistochemical (IHC) and in situ hybridization (ISH) assays. The luciferase assays were used to prove KLF12 as the downstream target of miR-141. The cDNA microarray and apoptotic protein arrays were used to identify the targets of miR-141 and KLF12. The competition of KLF12 and Sp1 on survivin promoter was examined by ChIP assay. IHC analysis on ovarian cancer tissue array was used to evaluate the expressions of KLF12 and miR-141 and to show the clinical relevance. The functional studies were performed by in vitro and in vivo tumorigenic assays.

Results

Enforced expression of miR-141 promotes, while knockdown of miR-141 expression inhibits, cell proliferation, anchorage-independent capacity, anoikis resistance, tumor growth and peritoneal metastases of ovarian cancer cells. Bioinformatics and functional analysis identified that Kruppel-related zinc finger protein AP-2rep (KLF12) is directly targeted by miR-141. Consistent with this finding, knockdown of KLF12 phenocopied the effects of miR-141 overexpression in ovarian cancer cells. In contrast, restoration of KLF12 in miR-141-expressing cells significantly attenuated anoikis resistance in ovarian cancer cells via interfering with Sp1-mediated survivin transcription, which inhibits the intrinsic apoptotic pathway and is crucial for ovarian cancer cell survival, anoikis resistance and peritoneal metastases. Immunohistochemical (IHC) and in situ hybridization (ISH) assays confirmed that miRNA-141 expression is inversely correlated with KLF12 expression and significantly associated with advanced ovarian cancers accompanied with distal metastases, underscoring the clinical relevance of our findings.

Conclusions

Our data identify a novel signaling axis of miR-141/KLF12/Sp1/survivin in enhancing anoikis resistance and likely serves as a potential therapeutic target for metastatic ovarian cancer.
Appendix
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Literature
1.
Pereira A, Magrina JF, Magtibay PM, Perez-Medina T, Fernandez A, Peregrin I. The impact of peritoneal metastases in epithelial ovarian cancer with positive nodes. Int J Gynecol Cancer. 2011;21(8):1375–9.CrossRefPubMed
2.
Ursini-Siegel J, Siegel PM. The influence of the pre-metastatic niche on breast cancer metastasis. Cancer Lett. 2015;380(1):281–8.CrossRefPubMed
3.
Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3(6):453–8.CrossRefPubMed
4.
Simpson CD, Anyiwe K, Schimmer AD. Anoikis resistance and tumor metastasis. Cancer Lett. 2008;272(2):177–85.CrossRefPubMed
5.
6.
Spring BQ, Abu-Yousif AO, Palanisami A, Rizvi I, Zheng X, Mai Z, Anbil S, Sears RB, Mensah LB, Goldschmidt R, et al. Selective treatment and monitoring of disseminated cancer micrometastases in vivo using dual-function, activatable immunoconjugates. Proc Natl Acad Sci U S A. 2014;111(10):E933–942.CrossRefPubMedPubMedCentral
7.
8.
Sugarbaker PH. Management of peritoneal metastases - Basic concepts. J BUON. 2015;20 Suppl 1:S2–11.PubMed
9.
Lu YF, Zhang L, Waye MM, Fu WM, Zhang JF. MiR-218 mediates tumorigenesis and metastasis: perspectives and implications. Exp Cell Res. 2015;334(1):173–82.CrossRefPubMed
10.
11.
Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, Hayward DC, Ball EE, Degnan B, Muller P, et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature. 2000;408(6808):86–9.CrossRefPubMed
12.
Pasquinelli AE. MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet. 2012;13(4):271–82.PubMed
13.
Huntzinger E, Izaurralde E. Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet. 2011;12(2):99–110.CrossRefPubMed
14.
Yang W, Lee DY, Ben-David Y. The roles of microRNAs in tumorigenesis and angiogenesis. Int J Physiol Pathophysiol Pharmacol. 2011;3(2):140–55.PubMed
15.
Rao X, Di Leva G, Li M, Fang F, Devlin C, Hartman-Frey C, Burow ME, Ivan M, Croce CM, Nephew KP. MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways. Oncogene. 2011;30(9):1082–97.CrossRefPubMed
16.
Garofalo M, Di Leva G, Romano G, Nuovo G, Suh SS, Ngankeu A, Taccioli C, Pichiorri F, Alder H, Secchiero P, et al. miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell. 2009;16(6):498–509.CrossRefPubMedPubMedCentral
17.
Sun T, Yang M, Chen S, Balk S, Pomerantz M, Hsieh CL, Brown M, Lee GS, Kantoff PW. The altered expression of MiR-221/-222 and MiR-23b/-27b is associated with the development of human castration resistant prostate cancer. Prostate. 2012;72(10):1093–103.
18.
Quintavalle C, Garofalo M, Zanca C, Romano G, Iaboni M, Del Basso De Caro M, Martinez-Montero JC, Incoronato M, Nuovo G, Croce CM, et al. miR-221/222 overexpession in human glioblastoma increases invasiveness by targeting the protein phosphate PTPmu. Oncogene. 2012;31(7):858–68.CrossRefPubMed
19.
Lee JW, Park YA, Choi JJ, Lee YY, Kim CJ, Choi C, Kim TJ, Lee NW, Kim BG, Bae DS. The expression of the miRNA-200 family in endometrial endometrioid carcinoma. Gynecol Oncol. 2011;120(1):56–62.CrossRefPubMed
20.
Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, Goodall GJ. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10(5):593–601.CrossRefPubMed
21.
Tsao SW, Mok SC, Fey EG, Fletcher JA, Wan TS, Chew EC, Muto MG, Knapp RC, Berkowitz RS. Characterization of human ovarian surface epithelial cells immortalized by human papilloma viral oncogenes (HPV-E6E7 ORFs). Exp Cell Res. 1995;218(2):499–507.CrossRefPubMed
22.
Liu MX, Siu MK, Liu SS, Yam JW, Ngan HY, Chan DW. Epigenetic silencing of microRNA-199b-5p is associated with acquired chemoresistance via activation of JAG1-Notch1 signaling in ovarian cancer. Oncotarget. 2014;5(4):944–58.CrossRefPubMed
23.
Nam EJ, Yoon H, Kim SW, Kim H, Kim YT, Kim JH, Kim JW, Kim S. MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res. 2008;14(9):2690–5.CrossRefPubMed
24.
da Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1):44–57.CrossRef
25.
Kumar A, Wong AK, Tizard ML, Moore RJ, Lefevre C. miRNA_Targets: a database for miRNA target predictions in coding and non-coding regions of mRNAs. Genomics. 2012;100(6):352–6.CrossRefPubMed
26.
Loddo M, Andryszkiewicz J, Rodriguez-Acebes S, Stoeber K, Jones A, Dafou D, Apostolidou S, Wollenschlaeger A, Widschwendter M, Sainsbury R, et al. Pregnancy-associated plasma protein A regulates mitosis and is epigenetically silenced in breast cancer. J Pathol. 2014;233(4):344–56.CrossRefPubMed
27.
Zhang Y, Chen B, Ming L, Qin H, Zheng L, Yue Z, Cheng Z, Wang Y, Zhang D, Liu C, et al. MicroRNA-141 inhibits vascular smooth muscle cell proliferation through targeting PAPP-A. Int J Clin Exp Pathol. 2015;8(11):14401–8.PubMedPubMedCentral
28.
Wang Z, Lei H, Sun Q. MicroRNA-141 and its associated gene FUS modulate proliferation, migration and cisplatin chemosensitivity in neuroblastoma cell lines. Oncol Rep. 2016;35(5):2943–51.PubMedPubMedCentral
29.
Wu PP, Zhu HY, Sun XF, Chen LX, Zhou Q, Chen J. MicroRNA-141 regulates the tumour suppressor DLC1 in colorectal cancer. Neoplasma. 2015;62(5):705–12.CrossRefPubMed
30.
Dong S, Meng X, Xue S, Yan Z, Ren P, Liu J. microRNA-141 inhibits thyroid cancer cell growth and metastasis by targeting insulin receptor substrate 2. Am J Transl Res. 2016;8(3):1471–81.PubMedPubMedCentral
31.
Cheng H, Liu P, Wang ZC, Zou L, Santiago S, Garbitt V, Gjoerup OV, Iglehart JD, Miron A, Richardson AL, et al. SIK1 couples LKB1 to p53-dependent anoikis and suppresses metastasis. Sci Signal. 2009;2(80):ra35.CrossRefPubMedPubMedCentral
32.
Li JH, Liu S, Zhou H, Qu LH, Yang JH. starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res. 2014;42(Database issue):D92–97.CrossRefPubMed
33.
Yang JH, Li JH, Shao P, Zhou H, Chen YQ, Qu LH. starBase: a database for exploring microRNA-mRNA interaction maps from Argonaute CLIP-Seq and Degradome-Seq data. Nucleic Acids Res. 2011;39(Database issue):D202–209.CrossRefPubMed
34.
Frisch SM, Francis H. Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol. 1994;124(4):619–26.CrossRefPubMed
35.
Guadamillas MC, Cerezo A, Del Pozo MA. Overcoming anoikis--pathways to anchorage-independent growth in cancer. J Cell Sci. 2011;124(Pt 19):3189–97.CrossRefPubMed
36.
Tetreault MP, Yang Y, Katz JP. Kruppel-like factors in cancer. Nat Rev Cancer. 2013;13(10):701–13.CrossRefPubMed
37.
Altieri DC. Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer. 2008;8(1):61–70.CrossRefPubMed
38.
Dohi T, Okada K, Xia F, Wilford CE, Samuel T, Welsh K, Marusawa H, Zou H, Armstrong R, Matsuzawa S, et al. An IAP-IAP complex inhibits apoptosis. J Biol Chem. 2004;279(33):34087–90.CrossRefPubMed
39.
Suske G, Bruford E, Philipsen S. Mammalian SP/KLF transcription factors: bring in the family. Genomics. 2005;85(5):551–6.CrossRefPubMed
40.
Mityaev MV, Kopantzev EP, Buzdin AA, Vinogradova TV, Sverdlov ED. Functional significance of a putative sp1 transcription factor binding site in the survivin gene promoter. Biochem Biokhim. 2008;73(11):1183–91.CrossRef
41.
Xia H, Chen S, Huang H, Ma H. Survivin over-expression is correlated with a poor prognosis in esophageal cancer patients. Clin Chim Acta. 2015;446:82–5.CrossRefPubMed
42.
Tsubaki M, Takeda T, Ogawa N, Sakamoto K, Shimaoka H, Fujita A, Itoh T, Imano M, Ishizaka T, Satou T, et al. Overexpression of survivin via activation of ERK1/2, Akt, and NF-kappaB plays a central role in vincristine resistance in multiple myeloma cells. Leuk Res. 2015;39(4):445–52.CrossRefPubMed
43.
Ye Q, Cai W, Zheng Y, Evers BM, She QB. ERK and AKT signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer. Oncogene. 2014;33(14):1828–39.CrossRefPubMed
44.
Jiang Q, Dai L, Cheng L, Chen X, Li Y, Zhang S, Su X, Zhao X, Wei Y, Deng H. Efficient inhibition of intraperitoneal ovarian cancer growth in nude mice by liposomal delivery of short hairpin RNA against STAT3. J Obstet Gynaecol Res. 2013;39(3):701–9.CrossRefPubMed
45.
Paoli P, Giannoni E, Chiarugi P. Anoikis molecular pathways and its role in cancer progression. Biochim Biophys Acta. 2013;1833(12):3481–98.CrossRefPubMed
46.
Tan K, Goldstein D, Crowe P, Yang JL. Uncovering a key to the process of metastasis in human cancers: a review of critical regulators of anoikis. J Cancer Res Clin Oncol. 2013;139(11):1795–805.CrossRefPubMed
47.
Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, Taccioli C, Volinia S, Liu CG, Alder H, et al. MicroRNA signatures in human ovarian cancer. Cancer Res. 2007;67(18):8699–707.CrossRefPubMed
48.
49.
Feng X, Wang Z, Fillmore R, Xi Y. MiR-200, a new star miRNA in human cancer. Cancer Lett. 2014;344(2):166–73.CrossRefPubMed
50.
51.
Katz L. Special issue dedicated to Sir David Alan Hopwood. J Ind Microbiol Biotechnol. 2014;41(2):173–477.
52.
Chen J, Wang L, Matyunina LV, Hill CG, McDonald JF. Overexpression of miR-429 induces mesenchymal-to-epithelial transition (MET) in metastatic ovarian cancer cells. Gynecol Oncol. 2011;121(1):200–5.CrossRefPubMed
53.
54.
Dykxhoorn DM, Wu Y, Xie H, Yu F, Lal A, Petrocca F, Martinvalet D, Song E, Lim B, Lieberman J. miR-200 enhances mouse breast cancer cell colonization to form distant metastases. PLoS One. 2009;4(9):e7181.CrossRefPubMedPubMedCentral
55.
Mateescu B, Batista L, Cardon M, Gruosso T, de Feraudy Y, Mariani O, Nicolas A, Meyniel JP, Cottu P, Sastre-Garau X, et al. miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response. Nat Med. 2011;17(12):1627–35.CrossRefPubMed
56.
van Jaarsveld MT, Helleman J, Boersma AW, van Kuijk PF, van Ijcken WF, Despierre E, Vergote I, Mathijssen RH, Berns EM, Verweij J, et al. miR-141 regulates KEAP1 and modulates cisplatin sensitivity in ovarian cancer cells. Oncogene. 2013;32(36):4284–93.CrossRefPubMed
57.
Koutsaki M, Spandidos DA, Zaravinos A. Epithelial-mesenchymal transition-associated miRNAs in ovarian carcinoma, with highlight on the miR-200 family: prognostic value and prospective role in ovarian cancer therapeutics. Cancer Lett. 2014;351(2):173–81.CrossRefPubMed
58.
Wang L, Mezencev R, Svajdler M, Benigno BB, McDonald JF. Ectopic over-expression of miR-429 induces mesenchymal-to-epithelial transition (MET) and increased drug sensitivity in metastasizing ovarian cancer cells. Gynecol Oncol. 2014;134(1):96–103.CrossRefPubMed
59.
Iwama H. Coordinated networks of microRNAs and transcription factors with evolutionary perspectives. Adv Exp Med Biol. 2013;774:169–87.CrossRefPubMed
60.
Limame R, Op de Beeck K, Lardon F, De Wever O, Pauwels P. Kruppel-like factors in cancer progression: three fingers on the steering wheel. Oncotarget. 2014;5(1):29–48.PubMed
61.
Godin-Heymann N, Brabetz S, Murillo MM, Saponaro M, Santos CR, Lobley A, East P, Chakravarty P, Matthews N, Kelly G, et al. Tumour-suppression function of KLF12 through regulation of anoikis. Oncogene. 2016;35(25):3324–34.
62.
Gu X, Lin HL. Analysis of survivin expression in subtypes of lymphoma. Ai Zheng. 2004;23(6):655–61.PubMed
63.
Sarela AI, Macadam RC, Farmery SM, Markham AF, Guillou PJ. Expression of the antiapoptosis gene, survivin, predicts death from recurrent colorectal carcinoma. Gut. 2000;46(5):645–50.CrossRefPubMedPubMedCentral
64.
65.
Chen L, Liang L, Yan X, Liu N, Gong L, Pan S, Lin F, Zhang Q, Zhao H, Zheng F. Survivin status affects prognosis and chemosensitivity in epithelial ovarian cancer. Int J Gynecol Cancer. 2013;23(2):256–63.CrossRefPubMed
Metadata
Title
MicroRNA-141 enhances anoikis resistance in metastatic progression of ovarian cancer through targeting KLF12/Sp1/survivin axis
Authors
Celia S. L. Mak
Mingo M. H. Yung
Lynn M. N. Hui
Leanne L. Leung
Rui Liang
Kangmei Chen
Stephanie S. Liu
Yiming Qin
Thomas H. Y. Leung
Kai-Fai Lee
Karen K. L. Chan
Hextan Y. S. Ngan
David W. Chan
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2017
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-017-0582-2

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