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Original Article FAT1 Inhibits the Proliferation and Metastasis of Cervical Cancer Cells by Binding Β-Catenin

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Original Article FAT1 Inhibits the Proliferation and Metastasis of Cervical Cancer Cells by Binding Β-Catenin Int J Clin Exp Pathol 2019;12(10):3807-3818 www.ijcep.com /ISSN:1936-2625/IJCEP0099984 Original Article FAT1 inhibits the proliferation and metastasis of cervical cancer cells by binding β-catenin Mengyue Chen, Xinwei Sun, Yanzhou Wang, Kaijian Ling, Cheng Chen, Xiongwei Cai, Xiaolong Liang, Zhiqing Liang Department of Obstetrics & Gynaecology, Southwest Hospital, Army Medical University, Chongqing, China Received July 23, 2019; Accepted August 29, 2019; Epub October 1, 2019; Published October 15, 2019 Abstract: FAT1 is a mutant gene found frequently in human cervical cancer (CC), but its expression and relevance in CC proliferation, invasion, and migration are still unknown. We aimed to explore the role and novel mechanism of FAT1 in CC progression. The expression of FAT1 in CC and adjacent normal tissues was analysed, and we inves- tigated the proliferation, migration, and invasion of HeLa and C33A cells treated with wild-type FAT1 plasmid or FAT1 siRNA. Meanwhile, we evaluated the effect of FAT1 on the epithelial-mesenchymal transition (EMT) and the β-catenin-mediated transcription of target genes. Here, we showed that FAT1 expression was significantly lower in CC tissues than in adjacent tissues. FAT1 overexpression significantly dysregulated CC cell proliferation, invasion, and migration, whereas FAT1 knockdown had the opposite effect. FAT1 overexpression promoted the expression of phosphorylated β-catenin and E-cadherin protein and inhibited the expression of vimentin, TWIST, and several downstream targets of β-catenin, namely, c-MYC, TCF-4 and MMP14. In contrast, FAT1 silencing notably increased the expression c-MYC, TCF-4, and MMP14 and promoted the EMT in HeLa and C33A cells. Endogenous and exog- enous FAT1 was confirmed to interact with β-catenin, and the overexpression of β-catenin could partially block the effect of FAT1 on the proliferation, migration, and invasion of HeLa and C33A cells. Conclusion: FAT1 acts as a tumor suppressor by inhibiting β-catenin-mediated transcription and might be used as a novel anti-metastatic agent in targeted CC therapy. Keywords: Cervical cancer, FAT1, β-catenin, metastasis, epithelial-mesenchymal transition Introduction differently in human cancer cells. Our prelimi- nary work showed that the mutation rate of Cervical cancer (CC) is one of the most com- FAT1 was 8.8%. Notably, FAT1 mutations, in- mon gynecologic cancers and is the fourth cluding termination (44%) and missense (56%) leading cause of mortality in women worldwide. mutations, occurred in the functional area. A The survival rates for International Federation previous study showed that the expression of of Gynecology and Obstetrics (FIGO) stage I FAT1 was downregulated in intrahepatic cholan- patients are reported as 80-98% but decrease giocarcinoma tissue [22], oral cancer cell lines, markedly to 50% when patients also have primary oral cancers (Nakaya et al. 2005) and metastasis [4]. Although many patients have astrocytic tumors [6]. In contrast, Fat1 protein greatly benefitted from surgery and chemora- is expressed in leukemia cell lines, such as diotherapy, the recurrence and metastasis Jurkat and THP-1 cells, whereas no visible rates remain high (approximately 29% to 38%) expression of FAT1 is detected in normal periph- and are the main causes of death [32]. Thus, eral blood and bone marrow cells [7]. Me- the molecular pathogenesis underlying CC pro- chanically, FAT1 plays a dual role in difference gression must be identified to elucidate new cancers by the Hippo, Wnt, and MAPK/ERK sig- therapeutic targets. nalling pathways [1, 11, 17]. It is conventionally considered to be a tumor suppressor gene in FAT1, a member of the FAT cadherin superfam- oral cancer [6], head and neck squamous cell ily, is a ~500-kD transmembrane protein that carcinoma [9], and astrocytic tumors [6], among regulates actin dynamics, cell-cell adhesion, others [18]. Conversely, FAT1 is also considered and cell polarity [13, 24, 26]. FAT1 is expressed an oncogene that promotes acute myeloid leu- FAT1 inhibits proliferation and metastasis of cervical cancer cells kaemia and acute lymphoblastic leukaemia were purchased from Sigma-Aldrich (Shang- proliferation [7], modulates epithelial-mesen- hai, China). Other primary antibodies, including chymal transition (EMT) and the expression of E-cadherin, vimentin, TWIST, total β-catenin stemness-related genes in hypoxic glioblasto- and phospho-β-catenin (p-β-catenin), transcrip- ma [25]. To date, the role and mechanisms of tion factor 4 (TCF-4), matrix metalloprotein- FAT1 in CC remain unclear. ase-14 (MMP-14), c-Myc and β-actin antibod- ies, were purchased from CST Co., Ltd. (Sh- The Wnt signalling pathway is highly conserved anghai, China). A RevertAidTM First Strand and critical for cell proliferation, differentiation, cDNA Synthesis Kit and Protein Extraction Re- invasion and migration [5, 29, 31]. As a canoni- agent for Mammalian, RPMI 1640 Medium, cal mediator of the Wnt pathway, β-catenin Minimum Essential Media (MEM), fetal bovine plays a key role in Wnt signal transduction cas- serum (FBS), Opti-MEM and 0.25% trypsin were cades and the activation of the transcription of ordered from Thermo Fisher Scientific Co., Ltd. downstream target genes, such as T cell factor/ (Shanghai, China). PCR Mix for real-time PCR lymphoid enhancer factor (TCF/LEF) and c-Myc, was purchased from Roche (Basel, Switzerland). after its stabilization in the cytoplasm and Transwell® inserts were purchased from translocation into the nucleus [21]. MacDonald Corning Co., Ltd. (New York, USA). Protein beads et al. showed that aberrant activation of the (A/G PLUS-Agarose) were purchased from Wnt/β-catenin signalling pathway contributes Santa Cruz Biotechnology (Santa Cruz, CA, to many cancers [16]. Shinohara and col- USA). HRP-conjugated secondary antibodies leagues revealed that β-catenin is notably were purchased from Beijing Golden Bridge accumulated in the cytoplasm and nucleus in Biotech (Beijing, China). Immobilon Western 47% of cervical cancer tissues [23]. Moreover, Chemiluminescent HRP Substrate was purch- nuclear expression of β-catenin is related to ased from Merck KGaA (Darmstadt, Germany). poor prognosis and chemo/radioresistance in ViaFect™ transfection reagent was ordered human CC [34]. Other studies have demon- from Promega Co., Ltd. (Madison, WI, USA). strated that the inhibition of β-catenin could pcDNA3.1-FAT1, pcDNA3.1(+)-β-catenin and suppress the proliferation, migration, and inva- pcDNA3.1(+) (vector) plasmids were constru- sion of CC cells [12, 27, 28, 30]. These data cted by Sangon Biotech Co., Ltd. (Shanghai, hint that β-catenin plays a critical role in con- China). Other reagents were from Sigma-Aldrich trolling the fate of CC. However, the mechanism and used as received (Shanghai, China). underlying the aberrant activation of the β-catenin signaling pathway and the regulation RNA isolation and Real-time PCR of β-catenin in CC cells remains unclear. Total RNA was isolated from CC tissues, adja- In this study, we aimed to determine the expres- cent nontumor tissues, and harvested cells, sion and function of FAT1 and evaluated the and cDNA was synthesized according to a pre- relationship between FAT1 and β-catenin in CC vious report [14]. The following primers: FAT1 cells as well as the underlying molecular mech- forward: 5’-CCTTCCAACAGCCACATCCACTAC-3’, anism. Taken together, the data demonstrate reverse: 5’-TTGAACCGTGAGCGTGTAACCTG-3’; that FAT1 severs as a tumor suppressor in CC β-actin forward: 5’-GAGCACAGAGCCTCGCCTTT- by promoting the phosphorylation of β-catenin. 3’, reverse: 5’-AGAGGCGTACAGGGATAGCA-3’. FAT1 gene expression was normalized to that Materials and methods of β-actin. Materials and samples Immunohistochemistry (IHC) 40 CC patients’ tumor and adjacent tissues IHC assay was carried out as previously des- were collected in the Department of Obstet- cribed [33]. Briefly, tissue sections were depar- rics & Gynecology, Southwest Hospital, Army affinized in xylene and rehydrated. After anti- Medical University. Patients who were enrolled gen retrieval, the samples blocked with 10% provided written informed consent, and the BSA. The sections incubated with the primary Ethical Committee of Southwest Hospital of antibody for FAT1. Finally, the bound antibodies the Third Military Medical University approved were stained with diaminobenzidine (DAB), and the study (approval number: KY201336). TRI the sections were counterstained with hema- Reagent, CCK-8 and anti-FAT1 primary antibody toxylin. Each experiment was repeated 3 times. 3808 Int J Clin Exp Pathol 2019;12(10):3807-3818 FAT1 inhibits proliferation and metastasis of cervical cancer cells Cell cultures tional 48 h. After removing the medium, 100 μL of fresh medium with 10 μL of CCK-8 reagent HeLa (HPV18+) cells were purchased from a was added to each well, and then incubated at typical Cell Culture Collection Committee of the 37°C for 4 h. Finally, each well’s absorbance at Chinese Academy of Sciences Library, and 450 nm was detected. C33A (HPV-) CC cells were obtained from ATCC. These cells had been identified by STR. Hela Migration and invasion assays and C-33A cells were identified again by Ge- nechem and Fuheng Biology Co. Ltd in October The ability of cell migration and invasion was 2017 and November 2018, respectively. These determined by transwell assay according to cells were cultured in RPMI 1640 or MEM con- manufacturer’s instructions. 5 × 103 cells in taining 10% FBS at 37°C in 5% CO2. 100 μL of serum-free medium were seeded
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