Expression of BMP7 in cervical cancer and inhibition of epithelial‑mesenchymal transition by BMP7 knockdown in HeLa cells

Sun,Rui; Guan,Hongwei; Liu,Wei; Liang,Junhui; Wang,Fei; Li,Changzhong

doi:10.3892/ijmm.2020.4519

Expression of BMP7 in cervical cancer and inhibition of epithelial‑mesenchymal transition by BMP7 knockdown in HeLa cells

Authors:
- Rui Sun
- Hongwei Guan
- Wei Liu
- Junhui Liang
- Fei Wang
- Changzhong Li
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Affiliations: Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
Published online on: February 27, 2020 https://doi.org/10.3892/ijmm.2020.4519
Pages: 1417-1424
Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the present study was to investigate the expression of bone morphogenetic protein 7 (BMP7) in cervical cancer tissues, the effect of BMP7 on the proliferation, migration and epithelial‑mesenchymal transition (EMT) of cervical cancer HeLa cells and the possible mechanism involved. Immunohistochemistry was used to stain the cervical cancer tissues and benign or precancerous lesions. Lentivirus containing BMP7 knockdown was transfected in HeLa cells and western blotting was performed to analyze BMP7 expression. At the same time, the influence of BMP7 knockdown on the expression of phosphorylated (p)‑mothers against decapentaplegic homolog 1/5/9 and EMT‑related markers [epithelial‑cadherin, neural‑cadherin, Vimentin, Snail and Slug] was detected. Cell Counting Kit‑8 was used to detect cell proliferation. Transwell migration and invasion assays were performed to measure cell invasion and migration. The cell cycle was detected by flow cytometry. Compared with normal cervical epithelial and paracancerous cells, the positive rate of BMP7 expression in cervical cancer tissues was significantly increased. As compared with the control group, the expression of BMP7 was decreased in HeLa cells transfected with lentivirus. The knockdown of BMP7 in cervical cancer HeLa cells inhibited cell proliferation, migration and invasion, resulted in G1 cell cycle arrest and reversed the EMT process. In addition, the expression of p‑Smad1/5/9 was significantly decreased in HeLa cells with BMP7 knockdown. BMP7 is expected to be a possible target for the treatment 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	Liu P: Big data evaluation of the clinical epidemiology of cervical cancer in mainland China. Chin J Pract Gynecol Obstet. 34:41–45. 2018.
3	Bragdon B, Moseychuk O, Saldanha S, King D, Julian J and Nohe A: Bone morphogenetic proteins: A critical review. Cell Signal. 23:609–620. 2011. View Article : Google Scholar
4	Sunde JS, Donninger H, Wu K, Johnson ME, Pestell RG, Rose GS, Mok SC, Brady J, Bonome T and Birrer MJ: Expression profiling identifies altered expression of genes that contribute to the inhibition of transforming growth factor-beta signaling in ovarian cancer. Cancer Res. 66:8404–8412. 2006. View Article : Google Scholar : PubMed/NCBI
5	Cheng L, Lu W, Kulkarni B, Pejovic T, Yan X, Chiang JH, Hood L, Odunsi K and Lin B: Analysis of chemotherapy response programs in ovarian cancers by the next-generation sequencing technologies. Gynecol Oncol. 117:159–169. 2010. View Article : Google Scholar : PubMed/NCBI
6	Megumi K, Ishigami S, Uchikado Y, Kita Y, Okumura H, Matsumoto M, Uenosono Y, Arigami T, Kijima Y, Kitazono M, et al: Clinicopathological significance of BMP7 expression in esophageal squamous cell carcinoma. Ann Surg Oncol. 19:2066–2071. 2012. View Article : Google Scholar :
7	Aoki M, Ishigami S, Uenosono Y, Arigami T, Uchikado Y, Kita Y, Kurahara H, Matsumoto M, Ueno S and Natsugoe S: Expression of BMP-7 in human gastric cancer and its clinical significance. Br J Cancer. 104:714–718. 2011. View Article : Google Scholar : PubMed/NCBI
8	Shen W, Pang H, Xin B, Duan L, Liu L and Zhang H: Biological effects of BMP7 on small-cell lung cancer cells and its bone metastasis. Int J Oncol. 53:1354–1362. 2018.PubMed/NCBI
9	Na YR, Seok SH, Kim DJ, Han JH, Kim TH, Jung H, Lee BH and Park JH: Bone morphogenetic protein 7 induces mesenchymal to-epithelial transition in melanoma cells, leading to inhibition of metastasis. Cancer Sci. 100:2218–2225. 2009. View Article : Google Scholar : PubMed/NCBI
10	Ying X, Sun Y and He P: Bone Morphogenetic Protein-7 inhibits EMT-associated genes in breast cancer. Cell Physiol Biochem. 37:1271–1278. 2015. View Article : Google Scholar : PubMed/NCBI
11	Kobayashi A, Okuda H, Xing F, Pandey PR, Watabe M, Hirota S, Pai SK, Liu W, Fukuda K, Chambers C, et al: Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp Med. 208:2641–2655. 2011. View Article : Google Scholar : PubMed/NCBI
12	Cassar L, Nicholls C, Pinto AR, Chen R, Wang L, Li H and Liu JP: TGF-beta receptor mediated telomerase inhibition, telomere shortening and breast cancer cell senescence. Protein Cell. 8:39–54. 2017. View Article : Google Scholar :
13	Sakai H, Furihata M, Matsuda C, Takahashi M, Miyazaki H, Konakahara T, Imamura T and Okada T: Augmented autocrine bone morphogenic protein (BMP) 7 signaling increases the metastatic potential of mouse breast cancer cells. Clin Exp Metastasis. 29:327–338. 2012. View Article : Google Scholar : PubMed/NCBI
14	Lim M, Chuong CM and Roy-Burman P: PI3K, Erk signaling in BMP7-induced epithelial-mesenchymal transition (EMT) of PC-3 prostate cancer cells in 2- and 3-dimensional cultures. Horm Cancer. 2:298–309. 2011. View Article : Google Scholar : PubMed/NCBI
15	Boon MR, van der Horst G, van der Pluijm G, Tamsma JT, Smit JW and Rensen PC: Bone morphogenetic protein 7: A broad-spectrum growth factor with multiple target therapeutic potency. Cytokine Growth Factor Rev. 22:221–229. 2011. View Article : Google Scholar : PubMed/NCBI
16	Cassar L, Li H, Pinto AR, Nicholls C, Bayne S and Liu JP: Bone morphogenetic protein-7 inhibits telomerase activity, telomere maintenance, and cervical tumor growth. Cancer Res. 68:9157–9166. 2008. View Article : Google Scholar : PubMed/NCBI
17	Miyazono K, Kusanagi K and Inoue H: Divergence and convergence of TGF-beta/BMP signaling. J Cell Physiol. 187:265–276. 2001. View Article : Google Scholar : PubMed/NCBI
18	Massagué J, Seoane J and Wotton D: Smad transcription factors. Genes Dev. 19:2783–2810. 2005. View Article : Google Scholar : PubMed/NCBI
19	Ruzinova MB and Benezra R: Id proteins in development, cell cycle and cancer. Trends Cell Biol. 13:410–418. 2003. View Article : Google Scholar : PubMed/NCBI
20	Roschger C and Cabrele C: The Id-protein family in developmental and cancer-associated pathways. Cell Commun Signal. 15:72017. View Article : Google Scholar : PubMed/NCBI
21	Xie L, Li J, Zhang Y, Liu B, Peng X, Lin Y, Xu W and Hu L: Inhibitors of differentiation-1 promotes nitrosopyrrolidine-induced transformation of HPV 16-immortalized cervical epithelial cell. Cancer Sci. 105:506–511. 2014. View Article : Google Scholar : PubMed/NCBI
22	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(W1): W98–W102. 2017. View Article : Google Scholar : PubMed/NCBI
23	Saitoh M: Involvement of partial EMT in cancer progression. J Biochem. 164:257–264. 2018. View Article : Google Scholar : PubMed/NCBI
24	Lamouille S, Xu J and Derynck R: Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 15:178–196. 2014. View Article : Google Scholar : PubMed/NCBI
25	Muthukrishnan SD, Yang X, Friesel R and Oxburgh L: Concurrent BMP7 and FGF9 signalling governs AP-1 function to promote self-renewal of nephron progenitor cells. Nat Commun. 6:100272015. View Article : Google Scholar : PubMed/NCBI
26	Alarmo EL, Pärssinen J, Ketolainen JM, Savinainen K, Karhu R and Kallioniemi A: BMP7 influences proliferation, migration, and invasion of breast cancer cells. Cancer Lett. 275:35–43. 2009. View Article : Google Scholar