FAM83A exerts tumor‑suppressive roles in cervical cancer by regulating integrins

Xu,Junfen; Xu,Junfen; Xu,Junfen; Xu,Junfen; Lu,Weiguo; Lu,Weiguo; Lu,Weiguo; Lu,Weiguo

doi:10.3892/ijo.2020.5078

FAM83A exerts tumor‑suppressive roles in cervical cancer by regulating integrins

Authors:
- Junfen Xu
- Weiguo Lu
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Affiliations: Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
Published online on: June 9, 2020 https://doi.org/10.3892/ijo.2020.5078
Pages: 509-521
Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Family with sequence similarity 83 member A (FAM83A) has been recently observed to be upregulated in various types of cancer and hypothesized to be serve as an oncogene. The present study aimed to determine the functional roles and the underlying molecular mechanism of FAM83A in cervical cancer. The results demonstrated that although FAM83A expression was increased in cervical cancer compared with normal tissues, the expression levels of FAM83A were decreased in patients with advanced FIGO stage, deep stromal invasion, poor differentiation and/or lymph node metastasis and negatively associated with short survival time of patients with cervical cancer. FAM83A knockdown promoted cell proliferative, migratory and invasive abilities of CaSki and HeLa cells. A mouse xenograft model demonstrated that FAM83A knockdown promoted tumor growth in vivo. Mechanistically, RNA sequencing results revealed that knockdown of FAM83A increased the transcription of genes mainly associated with oncogenesis‑associated pathways. In addition, FAM83A knockdown increased the protein levels of α1, α3, α5, β4 and β5 integrins in vitro and in vivo, and the expression of FAM83A was also negatively associated with the levels of these proteins in human cervical cancer tissue samples. In conclusion, the results of the present study suggested that FAM83A may exert a tumor‑suppressive role in cervical cancer by suppressing the expression of integrins, which may offer new insight into the biological basis of cervical cancer.

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1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ and Muñoz N: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 189:12–19. 1999. View Article : Google Scholar : PubMed/NCBI
3	Hutchinson DJ and Klein KC: Human papillomavirus disease and vaccines. Am J Health Syst Pharm. 65:2105–2112. 2008. View Article : Google Scholar : PubMed/NCBI
4	Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H and Unger ER: Centers for Disease Control and Prevention (CDC); Advisory Committee on Immunization Practices (ACIP): Quadrivalent human papillomavirus vaccine: Recommendations of the advisory committee on immunization practices (ACIP). MMWR Recomm Rep. 56:1–24. 2007.PubMed/NCBI
5	Xu J, Liu H, Yang Y, Wang X, Liu P, Li Y, Meyers C, Banerjee NS, Wang HK, Cam M, et al: Genome-wide profiling of cervical RNA-binding proteins identifies human papillomavirus regulation of RNASEH2A expression by viral E7 and E2F1. MBio. 10:2019. View Article : Google Scholar
6	Lee SY, Meier R, Furuta S, Lenburg ME, Kenny PA, Xu R and Bissell MJ: FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice. J Clin Invest. 122:3211–3220. 2012. View Article : Google Scholar : PubMed/NCBI
7	Fulcher LJ, Bozatzi P, Tachie-Menson T, Wu KZL, Cummins TD, Bufton JC, Pinkas DM, Dunbar K, Shrestha S, Wood NT, et al: The DUF1669 domain of FAM83 family proteins anchor casein kinase 1 isoforms. Sci Signal. 11:eaao23412018. View Article : Google Scholar : PubMed/NCBI
8	Li Y, Dong X, Yin Y, Su Y, Xu Q, Zhang Y, Pang X, Zhang Y and Chen W: BJ-TSA-9, a novel human tumor-specific gene, has potential as a biomarker of lung cancer. Neoplasia. 7:1073–1080. 2005. View Article : Google Scholar : PubMed/NCBI
9	Bartel CA and Jackson MW: HER2-positive breast cancer cells expressing elevated FAM83A are sensitive to FAM83A loss. PLoS One. 12:pp. e01767782017, View Article : Google Scholar : PubMed/NCBI
10	Grant S: FAM83A and FAM83B: Candidate oncogenes and TKI resistance mediators. J Clin Invest. 122:3048–3051. 2012. View Article : Google Scholar : PubMed/NCBI
11	Chen S, Huang J, Liu Z, Liang Q, Zhang N and Jin Y: FAM83A is amplified and promotes cancer stem cell-like traits and chemore-sistance in pancreatic cancer. Oncogenesis. 6:pp. e3002017, View Article : Google Scholar
12	Snijders AM, Lee SY, Hang B, Hao W, Bissell MJ and Mao JH: FAM83 family oncogenes are broadly involved in human cancers: An integrative multi-omics approach. Mol Oncol. 11:167–179. 2017. View Article : Google Scholar : PubMed/NCBI
13	Li Y, Xiao X, Ji X, Liu B and Amos CI: RNA-seq analysis of lung adenocarcinomas reveals different gene expression profiles between smoking and nonsmoking patients. Tumour Biol. 36:8993–9003. 2015. View Article : Google Scholar : PubMed/NCBI
14	Cipriano R, Miskimen KL, Bryson BL, Foy CR, Bartel CA and Jackson MW: Conserved oncogenic behavior of the FAM83 family regulates MAPK signaling in human cancer. Mol Cancer Res. 12:1156–1165. 2014. View Article : Google Scholar : PubMed/NCBI
15	Pawitan Y, Bjöhle J, Amler L, Borg AL, Egyhazi S, Hall P, Han X, Holmberg L, Huang F, Klaar S, et al: Gene expression profiling spares early breast cancer patients from adjuvant therapy: Derived and validated in two population-based cohorts. Breast Cancer Res. 7:R953–R964. 2005. View Article : Google Scholar : PubMed/NCBI
16	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
17	Zhou Q, Wang X, Yu Z, Wu X, Chen X, Li J, Zhu Z, Liu B and Su L: Transducin (β)-like 1 X-linked receptor 1 promotes gastric cancer progression via the ERK1/2 pathway. Oncogene. 36:1873–1886. 2017. View Article : Google Scholar
18	Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R and Salzberg SL: TopHat2: Accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 14:R362013. View Article : Google Scholar : PubMed/NCBI
19	Anders S and Huber W: Differential expression analysis for sequence count data. Genome Biol. 11:R1062010. View Article : Google Scholar : PubMed/NCBI
20	Robinson JT, Thorvaldsdóttir H, Winckler W, Guttman M, Lander ES, Getz G and Mesirov JP: Integrative genomics viewer. Nat Biotechnol. 29:24–26. 2011. View Article : Google Scholar : PubMed/NCBI
21	Fang Y, Yu H, Liang X, Xu J and Cai X: Chk1-induced CCNB1 overexpression promotes cell proliferation and tumor growth in human colorectal cancer. Cancer Biol Ther. 15:1268–1279. 2014. View Article : Google Scholar : PubMed/NCBI
22	Winograd-Katz SE, Fässler R, Geiger B and Legate KR: The integrin adhesome: From genes and proteins to human disease. Nat Rev Mol Cell Biol. 15:273–288. 2014. View Article : Google Scholar : PubMed/NCBI
23	Hamidi H and Ivaska J: Every step of the way: Integrins in cancer progression and metastasis. Nat Rev Cancer. 18:533–548. 2018. View Article : Google Scholar : PubMed/NCBI
24	Seguin L, Desgrosellier JS, Weis SM and Cheresh DA: Integrins and cancer: Regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol. 25:234–240. 2015. View Article : Google Scholar : PubMed/NCBI
25	Raab-Westphal S, Marshall JF and Goodman SL: Integrins as therapeutic targets: Successes and cancers. Cancers (Basel). 9. pp. 1102017, View Article : Google Scholar
26	Hamidi H, Pietilä M and Ivaska J: The complexity of integrins in cancer and new scopes for therapeutic targeting. Br J Cancer. 115:1017–1023. 2016. View Article : Google Scholar : PubMed/NCBI
27	Cipriano R, Graham J, Miskimen KL, Bryson BL, Bruntz RC, Scott SA, Brown HA, Stark GR and Jackson MW: FAM83B mediates EGFR- and RAS-driven oncogenic transformation. J Clin Invest. 122:3197–3210. 2012. View Article : Google Scholar : PubMed/NCBI
28	Bartel CA, Parameswaran N, Cipriano R and Jackson MW: FAM83 proteins: Fostering new interactions to drive oncogenic signaling and therapeutic resistance. Oncotarget. 7:52597–52612. 2016. View Article : Google Scholar : PubMed/NCBI
29	Tang Z, Li C, Kang B, Gao G, Li C and Zhang Z: GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 45:W98–W102. 2017. View Article : Google Scholar : PubMed/NCBI
30	Ojesina AI, Lichtenstein L, Freeman SS, Pedamallu CS, Imaz-Rosshandler I, Pugh TJ, Cherniack AD, Ambrogio L, Cibulskis K, Bertelsen B, et al: Landscape of genomic alterations in cervical carcinomas. Nature. 506:371–375. 2014. View Article : Google Scholar : PubMed/NCBI
31	Hu Z, Zhu D, Wang W, Li W, Jia W, Zeng X, Ding W, Yu L, Wang X, Wang L, et al: Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism. Nat Genet. 47:158–163. 2015. View Article : Google Scholar : PubMed/NCBI
32	Ito Y, Miyoshi E, Sasaki N, Kakudo K, Yoshida H, Tomoda C, Uruno T, Takamura Y, Miya A, Kobayashi K, et al: Polo-like kinase 1 overexpression is an early event in the progression of papillary carcinoma. Br J Cancer. 90:414–418. 2004. View Article : Google Scholar : PubMed/NCBI
33	de Cárcer G, Venkateswaran SV, Salgueiro L, El Bakkali A, Somogyi K, Rowald K, Montañés P, Sanclemente M, Escobar B, de Martino A, et al: Plk1 overexpression induces chromosomal instability and suppresses tumor development. Nat Commun. 9:30122018. View Article : Google Scholar : PubMed/NCBI
34	Munger K, Gwin TK and McLaughlin-Drubin ME: p16 in HPV-associated cancers. Oncotarget. 4:1864–1865. 2013. View Article : Google Scholar : PubMed/NCBI
35	Malhone C and Longatto-Filho A: Cervical, ovarian and endometrial tumor markers: Potential clinical value. Semin Ultrasound CT MR. 40:350–357. 2019. View Article : Google Scholar : PubMed/NCBI
36	van der Flier A and Sonnenberg A: Function and interactions of integrins. Cell Tissue Res. 305:285–298. 2001. View Article : Google Scholar : PubMed/NCBI
37	Hood JD and Cheresh DA: Role of integrins in cell invasion and migration. Nat Rev Cancer. 2:91–100. 2002. View Article : Google Scholar
38	Cagnet S, Faraldo MM, Kreft M, Sonnenberg A, Raymond K and Glukhova MA: Signaling events mediated by α3β1 integrin are essential for mammary tumorigenesis. Oncogene. 33:4286–4295. 2014. View Article : Google Scholar
39	White DE, Kurpios NA, Zuo D, Hassell JA, Blaess S, Mueller U and Muller WJ: Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. Cancer Cell. 6:159–170. 2004. View Article : Google Scholar : PubMed/NCBI
40	Roman J, Ritzenthaler JD, Roser-Page S, Sun X and Han S: alpha5beta1-integrin expression is essential for tumor progression in experimental lung cancer. Am J Respir Cell Mol Biol. 43:684–691. 2010. View Article : Google Scholar : PubMed/NCBI
41	Brooks PC, Clark RA and Cheresh DA: Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science. 264:569–571. 1994. View Article : Google Scholar : PubMed/NCBI
42	Trusolino L, Bertotti A and Comoglio PM: A signaling adapter function for alpha6beta4 integrin in the control of HGF-dependent invasive growth. Cell. 107:643–654. 2001. View Article : Google Scholar : PubMed/NCBI
43	Serini G, Trusolino L, Saggiorato E, Cremona O, De Rossi M, Angeli A, Orlandi F and Marchisio PC: Changes in integrin and E-cadherin expression in neoplastic versus normal thyroid tissue. J Natl Cancer Inst. 88:442–449. 1996. View Article : Google Scholar : PubMed/NCBI
44	Khwaja A, Rodriguez-Viciana P, Wennström S, Warne PH and Downward J: Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J. 16:2783–2793. 1997. View Article : Google Scholar : PubMed/NCBI
45	Shaw LM, Rabinovitz I, Wang HH, Toker A and Mercurio AM: Activation of phosphoinositide 3-OH kinase by the alpha6beta4 integrin promotes carcinoma invasion. Cell. 91:949–960. 1997. View Article : Google Scholar
46	Rathinam R and Alahari SK: Important role of integrins in the cancer biology. Cancer Metastasis Rev. 29:223–237. 2010. View Article : Google Scholar : PubMed/NCBI
47	FIGO Committee on Gynecologic Oncology: FIGO staging for carcinoma of the vulva, cervix, and corpus uteri. Int J Gynaecol Obstet. 125:97–98. 2014. View Article : Google Scholar : PubMed/NCBI