CBX7 is involved in the progression of cervical cancer through the ITGβ3/TGFβ1/AKT pathway

Tian,Ping; Deng,Jinglan; Ma,Cailing; Miershali,Ainipa; Maimaitirexiati,Gulikezi; Yan,Qi; Liu,Yating; Maimaiti,Hatimihan; Li,Yuting; Zhou,Changhui; Ren,Jingqin; Ding,Lu; Li,Rong

doi:10.3892/ol.2023.14147

CBX7 is involved in the progression of cervical cancer through the ITGβ3/TGFβ1/AKT pathway

Authors:
- Ping Tian
- Jinglan Deng
- Cailing Ma
- Ainipa Miershali
- Gulikezi Maimaitirexiati
- Qi Yan
- Yating Liu
- Hatimihan Maimaiti
- Yuting Li
- Changhui Zhou
- Jingqin Ren
- Lu Ding
- Rong Li
View Affiliations

Affiliations: State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, Xinjiang Uyghur Autonomous Region 830054, P.R. China, College of Nursing, Xinjiang Medical University, Urumqi, Xinjiang Uyghur Autonomous Region 830054, P.R. China, Department of Child, Adolescent and Maternal Hygiene, College of Public Health, Xinjiang Medical University, Urumqi, Xinjiang Uyghur Autonomous Region 830054, P.R. China, Department of Child, Adolescent and Maternal Hygiene, College of Public Health, Xinjiang Medical University, Urumqi, Xinjiang Uyghur Autonomous Region 830054, P.R. China, Postdoctoral Research Center on Public Health and Preventive Medicine, Xinjiang Medical University, Urumqi, Xinjiang Uyghur Autonomous Region 830054, P.R. China
Published online on: November 13, 2023 https://doi.org/10.3892/ol.2023.14147
Article Number: 14
Copyright: © Tian 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

The chromobox protein homolog 7 (CBX7) serves a tumor‑suppressive role in human malignant neoplasias. The downregulation of CBX7 is associated with the poor prognosis and aggressiveness of various human cancers. However, the biological functions and underlying mechanisms of CBX7 in cervical cancer remain unclear. The present study investigated the role and mechanism of CBX7 in cervical cancer. Lentivirus and siRNA were used to construct cervical cancer cells with stable CBX7 knockdown and SiHa xenograft models. The cell growth, migration, invasion and apoptosis were observed through in vivo and in vitro experiments. The expression levels of CBX7, integrin β3 (ITGβ3), transforming growth factor β1 (TGFβ1), phosphatidylinositol‑3‑kinase (PI3K), AKT, E‑cadherin (E‑cad) and vimentin (VIM) were detected by western blot analysis and reverse transcription‑quantitative PCR. The correlation between CBX7 and these genes was analyzed. TGFβ1 was also silenced through shRNA in cells with stable CBX7 knockdown to detect its effect on cell growth, invasion and apoptosis, and on pathway‑related gene expression. It was revealed that knockdown of CBX7 promoted the proliferation, migration, and invasion of cervical cancer cells, and inhibited apoptosis. In addition, CBX7 knockdown promoted tumor growth in vivo. Correlation analysis demonstrated that CBX7 was negatively correlated with ITGβ3, TGFβ1, PI3K, AKT, phosphorylated AKT and VIM, but positively correlated with E‑cad. Moreover, the knockdown of TGFβ1 reversed the promotion of cell proliferation and inhibition of apoptosis induced by CBX7 knockdown and attenuated the increase of ITGβ3, TGFβ1, PI3K, AKT and VIM caused by CBX7 knockdown. In conclusion, the findings of the present study indicated that the downregulation of CBX7 enhances cell migration and invasion while inhibiting cell apoptosis in cervical cancer by modulating the ITGβ3/TGFβ1/AKT signaling pathways.

View Figures

View References

1	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI
2	Razzaghi H, Saraiya M, Thompson TD, Henley SJ, Viens L and Wilson R: Five-year relative survival for human papillomavirus-associated cancer sites. Cancer. 124:203–211. 2018. View Article : Google Scholar : PubMed/NCBI
3	Lee BH: Commentary on: ‘Comprehensive molecular characterization of papillary renal-cell carcinoma.’ Cancer Genome Atlas Research Network. N Engl J Med. 2016 Jan 14;374((2)): 135–45. Urol Oncol. 35:578–579. 2017.
4	Forzati F, Federico A, Pallante P, Abbate A, Esposito F, Malapelle U, Sepe R, Palma G, Troncone G, Scarfò M, et al: CBX7 is a tumor suppressor in mice and humans. J Clin Invest. 122:612–623. 2012. View Article : Google Scholar : PubMed/NCBI
5	Iqbal MA, Siddiqui S, Ur Rehman A, Siddiqui FA, Singh P, Kumar B and Saluja D: Multiomics integrative analysis reveals antagonistic roles of CBX2 and CBX7 in metabolic reprogramming of breast cancer. Mol Oncol. 15:1450–1465. 2021. View Article : Google Scholar : PubMed/NCBI
6	Huang Z, Yan Y, Zhu Z, Liu J, He X, Dalangood S, Li M, Tan M, Cai J, Tang P, et al: CBX7 suppresses urinary bladder cancer progression via modulating AKR1B10-ERK signaling. Cell Death Dis. 12:5372021. View Article : Google Scholar : PubMed/NCBI
7	Forzati F, De Martino M, Esposito F, Sepe R, Pellecchia S, Malapelle U, Pellino G, Arra C and Fusco A: miR-155 is positively regulated by CBX7 in mouse embryonic fibroblasts and colon carcinomas, and targets the KRAS oncogene. BMC Cancer. 17:1702017. View Article : Google Scholar : PubMed/NCBI
8	Zheng ZQ, Yuan GQ, Kang NL, Nie QQ, Zhang GG and Wang Z: Chromobox 7/8 serve as independent indicators for glioblastoma via promoting proliferation and invasion of glioma cells. Front Neurol. 13:9120392022. View Article : Google Scholar : PubMed/NCBI
9	Yu T, Wu Y, Hu Q, Zhang J, Nie E, Wu W, Wang X, Wang Y and Liu N: CBX7 is a glioma prognostic marker and induces G1/S arrest via the silencing of CCNE1. Oncotarget. 8:26637–26647. 2017. View Article : Google Scholar : PubMed/NCBI
10	Li J, Xu Z, Zhou L and Hu K: Expression profile and prognostic values of Chromobox family members in human glioblastoma. Aging (Albany NY). 14:1910–1931. 2022. View Article : Google Scholar : PubMed/NCBI
11	Ni S, Wang H, Zhu X, Wan C, Xu J, Lu C, Xiao L, He J, Jiang C, Wang W and He Z: CBX7 suppresses cell proliferation, migration, and invasion through the inhibition of PTEN/Akt signaling in pancreatic cancer. Oncotarget. 8:8010–8021. 2017. View Article : Google Scholar : PubMed/NCBI
12	Cacciola NA, Sepe R, Forzati F, Federico A, Pellecchia S, Malapelle U, De Stefano A, Rocco D, Fusco A and Pallante P: Restoration of CBX7 expression increases the susceptibility of human lung carcinoma cells to irinotecan treatment. Naunyn Schmiedebergs Arch Pharmacol. 388:1179–1186. 2015. View Article : Google Scholar : PubMed/NCBI
13	Ni SJ, Zhao LQ, Wang XF, Wu ZH, Hua RX, Wan CH, Zhang JY, Zhang XW, Huang MZ, Gan L, et al: CBX7 regulates stem cell-like properties of gastric cancer cells via p16 and AKT-NF-κB-miR-21 pathways. J Hematol Oncol. 11:172018. View Article : Google Scholar : PubMed/NCBI
14	Scott CL, Gil J, Hernando E, Teruya-Feldstein J, Narita M, Martínez D, Visakorpi T, Mu D, Cordon-Cardo C, Peters G, et al: Role of the chromobox protein CBX7 in lymphomagenesis. Proc Natl Acad Sci USA. 104:5389–5394. 2007. View Article : Google Scholar : PubMed/NCBI
15	Gong L, Tang Y, Jiang L, Tang W and Luo S: Regulation of circGOLPH3 and its binding protein CBX7 on the proliferation and apoptosis of prostate cancer cells. Biosci Rep. 40:BSR202009362020. View Article : Google Scholar : PubMed/NCBI
16	Shinjo K, Yamashita Y, Yamamoto E, Akatsuka S, Uno N, Kamiya A, Niimi K, Sakaguchi Y, Nagasaka T, Takahashi T, et al: Expression of chromobox homolog 7 (CBX7) is associated with poor prognosis in ovarian clear cell adenocarcinoma via TRAIL-induced apoptotic pathway regulation. Int J Cancer. 135:308–318. 2014. View Article : Google Scholar : PubMed/NCBI
17	Mosbah A, Barakat R, Nabiel Y and Barakat G: High-risk and low-risk human papilloma virus in association to spontaneous preterm labor: A case-control study in a tertiary center, Egypt. J Matern Fetal Neonatal Med. 31:720–725. 2018. View Article : Google Scholar : PubMed/NCBI
18	Rapisarda V, Borghesan M, Miguela V, Encheva V, Snijders AP, Lujambio A and O'Loghlen A: Integrin Beta 3 regulates cellular senescence by activating the TGF-β pathway. Cell Rep. 18:2480–2493. 2017. View Article : Google Scholar : PubMed/NCBI
19	Xiao L, Zhu H, Shu J, Gong D, Zheng D and Gao J: Overexpression of TGF-β1 and SDF-1 in cervical cancer-associated fibroblasts promotes cell growth, invasion and migration. Arch Gynecol Obstet. 305:179–192. 2022. View Article : Google Scholar : PubMed/NCBI
20	You X, Wang Y, Meng J, Han S, Liu L, Sun Y, Zhang J, Sun S, Li X, Sun W, et al: Exosomal miR-663b exposed to TGF-β1 promotes cervical cancer metastasis and epithelial-mesenchymal transition by targeting MGAT3. Oncol Rep. 45:122021. View Article : Google Scholar : PubMed/NCBI
21	Gu R, Sun X, Chi Y, Zhou Q, Xiang H, Bosco DB, Lai X, Qin C, So KF, Ren Y and Chen XM: Integrin β3/Akt signaling contributes to platelet-induced hemangioendothelioma growth. Sci Rep. 7:64552017. View Article : Google Scholar : PubMed/NCBI
22	Tian P, Zhang C, Ma C, Ding L, Tao N, Ning L, Wang Y, Yong X, Yan Q, Lin X, et al: Decreased chromobox homologue 7 expression is associated with epithelial-mesenchymal transition and poor prognosis in cervical cancer. Open Med (Wars). 16:410–418. 2021. View Article : Google Scholar : PubMed/NCBI
23	Li R, Yan Q, Tian P, Wang Y, Wang J, Tao N, Ning L, Lin X, Ding L, Liu J and Ma C: CBX7 inhibits cell growth and motility and induces apoptosis in cervical cancer cells. Mol Ther Oncolytics. 15:108–116. 2019. View Article : Google Scholar : PubMed/NCBI
24	Larionov A, Krause A and Miller W: A standard curve based method for relative real time PCR data processing. BMC Bioinformatics. 6:622005. View Article : Google Scholar : PubMed/NCBI
25	Bao Z, Xu X, Liu Y, Chao H, Lin C, Li Z, You Y, Liu N and Ji J: CBX7 negatively regulates migration and invasion in glioma via Wnt/β-catenin pathway inactivation. Oncotarget. 8:39048–39063. 2017. View Article : Google Scholar : PubMed/NCBI
26	Tan C, Bei C, Zhu X, Zhang Y, Qin L and Tan S: Single nucleotide polymorphisms of CBX4 and CBX7 decrease the risk of hepatocellular carcinoma. Biomed Res Int. 2019:64368252019. View Article : Google Scholar : PubMed/NCBI
27	Pallante P, Forzati F, Federico A, Arra C and Fusco A: Polycomb protein family member CBX7 plays a critical role in cancer progression. Am J Cancer Res. 5:1594–1601. 2015.PubMed/NCBI
28	Huang Z, Liu J, Yang J, Yan Y, Yang C, He X, Huang R, Tan M, Wu D, Yan J and Shen B: PDE4B induces epithelial-to-mesenchymal transition in bladder cancer cells and is transcriptionally suppressed by CBX7. Front Cell Dev Biol. 9:7830502021. View Article : Google Scholar : PubMed/NCBI
29	Peng X, Guan L and Gao B: miRNA-19 promotes non-small-cell lung cancer cell proliferation via inhibiting CBX7 expression. Onco Targets Ther. 11:8865–8874. 2018. View Article : Google Scholar : PubMed/NCBI
30	Federico A, Sepe R, Cozzolino F, Piccolo C, Iannone C, Iacobucci I, Pucci P, Monti M and Fusco A: The complex CBX7-PRMT1 has a critical role in regulating E-cadherin gene expression and cell migration. Biochim Biophys Acta Gene Regul Mech. 1862:509–521. 2019. View Article : Google Scholar : PubMed/NCBI
31	Cicchini C, Amicone L, Alonzi T, Marchetti A, Mancone C and Tripodi M: Molecular mechanisms controlling the phenotype and the EMT/MET dynamics of hepatocyte. Liver Int. 35:302–310. 2015. View Article : Google Scholar : PubMed/NCBI
32	Wang C, Zhang J, Fok KL, Tsang LL, Ye M, Liu J, Li F, Zhao AZ, Chan HC and Chen H: cd147 induces epithelial-to-mesenchymal transition by disassembling cellular apoptosis susceptibility Protein/E-Cadherin/β-Catenin complex in human endometriosis. Am J Pathol. 188:1597–1607. 2018. View Article : Google Scholar : PubMed/NCBI
33	Jiang N, Pan W, Li J, Cao T and Shen H: Upregulated Circular RNA hsa_circ_0008433 regulates pathogenesis in endometriosis via miRNA. Reprod Sci. 27:2002–2017. 2020. View Article : Google Scholar : PubMed/NCBI
34	Vu T and Datta PK: Regulation of EMT in colorectal cancer: A culprit in metastasis. Cancers (Basel). 9:1712017. View Article : Google Scholar : PubMed/NCBI
35	Loh CY, Chai JY, Tang TF, Wong WF, Sethi G, Shanmugam MK, Chong PP and Looi CY: The E-Cadherin and N-Cadherin switch in epithelial-to-mesenchymal transition: signaling, therapeutic implications, and challenges. Cells. 8:11182019. View Article : Google Scholar : PubMed/NCBI
36	Luo R, Wei Y, Chen P, Zhang J, Wang L, Wang W, Wang P and Tian W: Mesenchymal stem cells inhibit epithelial-to-mesenchymal transition by modulating the IRE1α branch of the endoplasmic reticulum stress response. Stem Cells Int. 2023:44837762023. View Article : Google Scholar : PubMed/NCBI
37	E M Eid E, S Alanazi A, Koosha S, A Alrasheedy A, Azam F, M Taban I, Khalilullah H, Sadiq Al-Qubaisi M and A Alshawsh M: Zerumbone induces apoptosis in breast cancer cells by targeting αvβ3 integrin upon Co-administration with TP5-iRGD peptide. Molecules. 24:25542019. View Article : Google Scholar : PubMed/NCBI
38	Dehghani-Ghobadi Z, Sheikh Hasani S, Arefian E and Hossein G: Wnt5A and TGFβ1 Converges through YAP1 Activity and Integrin Alpha v Up-Regulation promoting epithelial to mesenchymal transition in ovarian cancer cells and mesothelial cell activation. Cells. 11:2372022. View Article : Google Scholar : PubMed/NCBI
39	Chen M, Wu C, Fu Z and Liu S: ICAM1 promotes bone metastasis via integrin-mediated TGF-β/EMT signaling in triple-negative breast cancer. Cancer Sci. 113:3751–3765. 2022. View Article : Google Scholar : PubMed/NCBI
40	Shidal C, Singh NP, Nagarkatti P and Nagarkatti M: MicroRNA-92 expression in CD133(+) melanoma stem cells regulates immunosuppression in the tumor microenvironment via integrin-dependent activation of TGFβ. Cancer Res. 79:3622–3635. 2019. View Article : Google Scholar : PubMed/NCBI
41	Fullar A, Dudas J, Olah L, Hollósi P, Papp Z, Sobel G, Karászi K, Paku S, Baghy K and Kovalszky I: Remodeling of extracellular matrix by normal and tumor-associated fibroblasts promotes cervical cancer progression. BMC Cancer. 15:2562015. View Article : Google Scholar : PubMed/NCBI
42	Ren J, Yu H, Li W, Jin X and Yan B: Downregulation of CBX7 induced by EZH2 upregulates FGFR3 expression to reduce sensitivity to cisplatin in bladder cancer. Br J Cancer. 128:232–244. 2023. View Article : Google Scholar : PubMed/NCBI
43	Chen LY, Cheng CS, Qu C, Wang P, Chen H, Meng ZQ and Chen Z: CBX3 promotes proliferation and regulates glycolysis via suppressing FBP1 in pancreatic cancer. Biochem Biophys Res Commun. 500:691–697. 2018. View Article : Google Scholar : PubMed/NCBI
44	Huang C, Su T, Xue Y, Cheng C, Lay FD, McKee RA, Li M, Vashisht A, Wohlschlegel J, Novitch BG, et al: Cbx3 maintains lineage specificity during neural differentiation. Genes Dev. 31:241–246. 2017. View Article : Google Scholar : PubMed/NCBI