Overexpression of SOCS4 inhibits proliferation and migration of cervical cancer cells by regulating JAK1/STAT3 signaling pathway

Purpose: To delve into the related molecular mechanism of suppressor of cytokine signaling 4 (SOCS4) on cervical cancer cell proliferation and migration. Methods: Quantitative real-time polymerase chain reaction and western blot assays were employed to examine SOCS4 mRNA or protein expression in four human cervical cancer cell line (HeLa, SW-732, AV3, and CaSki) and normal cervical epithelium immortalized cell line (H8) MTT cell viability assays were applied to verify the cell proliferation of HeLa after overexpression of SOCS4. Wound scratch healing assays and transwell assays were applied to examine cell migration and invasion of HeLa after overexpression of SOCS4. Flow cytometry and western blot assays were applied to check the role of SOCS4 in the apoptosis of cervical cancer cells. The western blot assays were applied to examine the protein expression of JAK1, p-JAK1, STAT3, and p-STAT3 in HeLa after overexpression of SOCS4. Results: In this study, the results revealed that the mRNA and protein expression level of SOCS4 was lower in four human cervical cancer cell line than normal cervical epithelium immortalized cell line, respectively. Overexpression of SOCS4 inhibited the proliferation migration, and invasion of cervical cancer cells as well as promotes apoptosis of cervical cancer cells. Meanwhile, overexpression of SOCS4 in HeLa would inhibit phosphorylation of JAK1 and STAT3 protein. Conclusion: SOCS4 inhibited the proliferation and migration of cervical cancer cells by regulating the JAK1/STAT3 pathway.

SOCS4; Cervical cancer; JAK1; STAT3

[1] Medina-Alarcón KP, Voltan AR, Fonseca-Santos B, Moro IJ, de Oliveira Souza F, Chorilli M, et al. Highlights in nanocarriers for the treatment against cervical cancer. Materials Science & Engineering: C. 2017; 80: 748–759.

[2] Vidya Priyadarsini R, Senthil Murugan R, Maitreyi S, Ramalingam K, Karunagaran D, Nagini S. The flavonoid quercetin induces cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells through p53 induction and NF-κB inhibition. European Journal of Pharmacology. 2010; 649: 84–91.

[3] Chemaitilly W, Cohen LE. Diagnosis of endocrine disease: endocrine late-effects of childhood cancer and its treatments. European Journal of Endocrinology. 2017; 176; R183–R203.

[4] Mutrikah N, Winarno H, Amalia T, Djakaria M. Conventional and conformal technique of external beam radiotherapy in locally advanced cervical cancer: dose distribution, tumor response, and side effects. Journal of Physics: Conference Series. 2017; 884: 012122.

[5] Patel V, McGurk M. Use of pentoxifylline and tocopherol in radiation-induced fibrosis and fibroatrophy. The British Journal of Oral & Maxillofacial Surgery. 2017; 55: 235–241.

[6] Sasi W, Sharma AK, Mokbel K. The role of suppressors of cytokine signalling in human neoplasms. Molecular Biology International. 2014; 2014: 630797.

[7] Xiao X, Yang D, Gong X, Mo D, Pan S, Xu J. miR-1290 promotes lung adenocarcinoma cell proliferation and invasion by targeting SOCS4. Oncotarget. 2018; 9: 11977–11988.

[8] Scheitz CJF, Lee TS, McDermitt DJ, Tumbar T. Defining a tissue stem cell-driven Runx1/Stat3 signalling axis in epithelial cancer. EMBO Journal. 2012; 31: 4124–4139.

[9] Ma J, Mannoor K, Gao L, Tan A, Guarnera MA, Zhan M, et al. Characterization of microRNA transcriptome in lung cancer by next-generation deep sequencing. Molecular Oncology. 2014; 8: 1208–1219.

[10] Lopez TV, Lappin TR, Maxwell P, Shi Z, Lopez-Marure R, Aguilar C, et al. Autocrine/paracrine erythropoietin signalling promotes JAK/STAT-dependent proliferation of human cervical cancer cells. International Journal of Cancer. 2011; 129: 2566– 2576.

[11] Chen B, Liang Y, He Z, An Y, Zhao W, Wu J. Autocrine activity of BDNF induced by the STAT3 signaling pathway causes prolonged TrkB activation and promotes human non-small-cell lung cancer proliferation. Scientific Reports. 2016; 6: 30404.

[12] Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nature Medicine. 2005; 11: 1314–1321.

[13] Liu R, Zeng Y, Lei Z, Wang L, Yang H, Liu Z, et al. JAK/STAT3 signaling is required for TGF-β-induced epithelial mesenchymal transition in lung cancer cells. International Journal of Oncology. 2014; 44: 1643–1651.

[14] Huang LL, Rao W. SiRNA interfering STAT3 enhances DDP sensitivity in cervical cancer cells. European Review for Medical and Pharmacological Sciences. 2018; 22, 4098–4106.

[15] Song W, Chen Y, Zhu G, Xie H, Yang Z, Li L. Exosome-mediated miR-9-5p promotes proliferation and migration of renal cancer cells both in vitro and in vivo by targeting SOCS4. Biochemical and Biophysical Research Communications. 2020; 529: 1216–1224.

[16] Wu X, Cai D, Zhang F, Li M, Wan Q. Long noncoding RNA TUSC7 inhibits cell proliferation, migration and invasion by regulating SOCS4 (SOCS5) expression through targeting miR-616 in endometrial carcinoma. Life Sciences. 2019; 231: 116549.

[17] Yuan F, Chen Y, Zhao Y, Liu Z, Nan C, Zheng B, et al. MicroRNA‐30a inhibits the liver cell proliferation and promotes cell apoptosis through the JAK/STAT signaling pathway by targeting SOCS‐1 in rats with sepsis. Journal of Cellular Physiology. 2019; 234: 17839–17853.

[18] Xing C, Zhang D, Gui S, Tao M. Kidney-replenishing herb induces SOCS-3 Expression via ERK/MAPK pathway and improves growth of the first-trimester human trophoblast cells. Evidence-Based Complementary and Alternative Medicine. 2017; 2017: 2473431.

[19] Guo W, Li W, Yuan L, Mei X, Hu W. MicroRNA-106a-3p Induces Apatinib Resistance and Activates Janus-Activated Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) by targeting the SOCS system in gastric cancer. Medical Science Monitor. 2019; 25: 10122–10128.

[20] Zheng H, Zheng X, Liu B. MiRNA-101 inhibits ovarian cancer cells proliferation and invasion by down-regulating expression of SOCS-2. International Journal of Clinical and Experimental Medicine. 2015; 8: 20263–20270.

[21] Souma Y, Nishida T, Serada S, Iwahori K, Takahashi T, Fujimoto M, et al. Antiproliferative effect of SOCS-1 through the suppression of STAT3 and p38 MAPK activation in gastric cancer cells. International Journal of Cancer. 2012; 131: 1287–1296.

[22] Morris R, Kershaw NJ, Babon JJ. The molecular details of cytokine signaling via the JAK/STAT pathway. Protein Science. 2018; 27: 1984–2009.

[23] Zhong H, Hao L, Li X, Wang C, Wu X. Anti-inflammatory role of trilobatin on lipopolysaccharide-induced acute lung injury through activation of AMPK/GSK3β-Nrf2 pathway. Signa Vitae. 2020; 16: 160–166.

[24] Zhang M, Liu S, Chua MS, Li H, Luo D, Wang S, et al. SOCS5 inhibition induces autophagy to impair metastasis in hepatocellular carcinoma cells via the PI3K/Akt/mTOR pathway. Cell Death & Disease. 2019; 10: 612.

[25] Puhr M, Santer FR, Neuwirt H, Marcias G, Hobisch A, Culig Z. SOCS-3 antagonises the proliferative and migratory effects of fibroblast growth factor-2 in prostate cancer by inhibition of p44/p42 MAPK signalling. Endocrine-Related Cancer. 2010; 17: 525–538.

[26] To KF, Chan MWY, Leung WK, Ng EKW, Yu J, Bai AHC, et al. Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line. British Journal of Cancer. 2004; 91: 1335–1341.