S100A7 promotes endometrial carcinoma progression by activating the MAPK signaling pathway

S100 calcium binding protein A7 (S100A7) has been proofed to play a carcinogenic role in several cancers. However, its role and the regulatory mechanism in Endometrial carcinoma (EC) was unknown. Western blot was applied to determine the expression of S100A7 and Mitogen-activated protein kinase (MAPK) pathway-related protein in EC cells. Functional in vitro experiments were conducted to explore the effects of S100A7 on cell proliferation, apoptosis, migration, invasion and angiogenesis in EC. As a result, S100A7 expression was dramatically up-regulated in EC cells. Overexpression of S100A7 enhanced EC cells proliferation, migration, invasion and angiogenesis, and suppressed cell apoptosis, as well as activated MAPK signaling pathway. Whereas, knockdown of S100A7 exerted the opposite effects. Our finding suggested that S100A7 may promote the malignant progression of EC by activating MAPK pathway, implying S100A7 has significant potential to be used as an emerging therapeutic target for EC treatment.

Endometrial carcinoma; S100A7; Proliferation; Apoptosis; Migration; Invasion; Angiogenesis

[1] Concin N, Matias-Guiu X, Vergote I, Cibula D, Mirza MR, Marnitz S, et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. International Journal of Gynecologic Cancer. 2021; 31: 12–39.

[2] Makker V, Taylor MH, Aghajanian C, Oaknin A, Mier J, Cohn AL, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. Journal of Clinical Oncology. 2020; 38: 2981–2992.

[3] Perera J, Hoskin P. Adjuvant therapy for high-risk endometrial carcinoma. Clinical Oncology. 2021; 33: 560–566.

[4] Liang X, Zeng H, Chen S, Jiang M, Liu S, Fan J. Ovarian metastasis risk factors in endometrial carcinoma: a systematic review and meta-analysis. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2021; 267: 245–255.

[5] Zhang Y, Zhao W, Chen Z, Zhao X, Ren P, Zhu M. Establishment and evaluation of a risk-scoring system for lymph node metastasis in early-stage endometrial carcinoma: achieving preoperative risk stratification. The Journal of Obstetrics and Gynaecology Research. 2020; 46: 2305–2313.

[6] Guo J, Cui X, Zhang X, Qian H, Duan H, Zhang Y. The clinical characteristics of endometrial cancer with extraperitoneal metastasis and the value of surgery in treatment. Technology in Cancer Research & Treatment. 2020; 19: 1–5.

[7] D’Amico F, Skarmoutsou E, Libra M. The S100A7 nuclear interactors in autoimmune diseases: a coevolutionary study in mammals. Immuno-genetics. 2022; 74: 271–284.

[8] Luo G, Tang M, Zhao Q, Lu L, Xie Y, Li Y, et al. Bone marrow adipocytes enhance osteolytic bone destruction by activating 1q21.3(S100a7/8/9-IL6R)-TLR4 pathway in lung cancer. Journal of Cancer Research and Clinical Oncology. 2020; 146: 2241–2253.

[9] Lu Z, Zheng S, Liu C, Wang X, Zhang G, Wang F, et al. S100A7 as a potential diagnostic and prognostic biomarker of esophageal squamous cell carcinoma promotes M2 macrophage infiltration and angiogenesis. Clinical and Translational Medicine. 2021; 11: e459.

[10] Dey KK, Bharti R, Dey G, Pal I, Rajesh Y, Chavan S, et al. S100A7 has an oncogenic role in oral squamous cell carcinoma by activating p38/MAPK and RAB2A signaling pathway. Cancer Gene Therapy. 2016; 23: 382–391.

[11] Asl ER, Amini M, Najafi S, Mansoori B, Mokhtarzadeh A, Mohammadi A, et al. Interplay between MAPK/ERK signaling pathway and MicroR-NAs: a crucial mechanism regulating cancer cell metabolism and tumor progression. Life Sciences. 2021; 278: 119499.

[12] Park H, Baek K. E3 ligases and deubiquitinating enzymes regulating the MAPK signaling pathway in cancers. BBA—Reviews on Cancer. 2022; 1877: 188736.

[13] Wang J, Xu P, Yang X, Yu Q, Xu X, Zou G, et al. Association of myometrial invasion with lymphovascular space invasion, lymph node metastasis, recurrence, and overall survival in endometrial cancer: a meta-analysis of 79 studies with 68,870 patients. Frontiers in Oncology. 2021; 11: 762329.

[14] Gonzalez LL, Garrie K, Turner MD. Role of S100 proteins in health and disease. BBA—Molecular Cell Research. 2020; 1867: 118677.

[15] Singh P, Ali SA. Multifunctional role of S100 protein family in the immune system: an update. Cells. 2022; 11: 2274.

[16] Doi S, Fujioka N, Ohtsuka S, Kondo R, Yamamoto M, Denda M, et al. Regulation of the tubulin polymerization-promoting protein by Ca2+/S100 proteins. Cell Calcium. 2021; 96: 102404.

[17] Allgöwer C, Kretz AL, von Karstedt S, Wittau M, Henne-Bruns D, Lemke J. Friend or foe: S100 proteins in cancer. Cancers. 2020; 12: 2037.

[18] Dowarha D, Chou RH, Yu C. S100A1 blocks the interaction between p53 and mdm2 and decreases cell proliferation activity. PLOS ONE. 2020; 15: e0234152.

[19] Meng D, Sun R, Liu G, Peng L, Zheng L, Xie P, et al. S100A14 suppresses metastasis of nasopharyngeal carcinoma by inhibition of NF-kB signaling through degradation of IRAK1. Oncogene. 2020; 39: 5307–5322.

[20] Huang G, Zhang J, Qing G, Liu D, Wang X, Chen Y, et al. S100A2 silencing relieves epithelial-mesenchymal transition in pulmonary fibrosis by inhibiting the Wnt/β-catenin signaling pathway. DNA and Cell Biology. 2021; 40: 18–25.

[21] Xu HY, Song HM, Zhou Q. Comprehensive analysis of the expression and prognosis for S100 in human ovarian cancer: a strobe study. Medicine. 2020; 99: e22777.

[22] Huang P, Xue J. Long non‑coding RNA FOXD2-AS1 regulates the tumorigenesis and progression of breast cancer via the S100 calcium binding protein A1/Hippo signaling pathway. International Journal of Molecular Medicine. 2020; 46: 1477–1489.

[23] Cong Y, Cui Y, Wang S, Jiang L, Cao J, Zhu S, et al. Calcium-binding protein S100P promotes tumor progression but enhances chemosensitivity in breast cancer. Frontiers in Oncology. 2020; 10: 566302.

[24] Sun Q, Cao Y, Lan Y, Lei L, Zhang B, Wang S. S100A7 promotes the development of human endometriosis by activating NF-κB signaling pathway in endometrial stromal cells. Cell Biology International. 2021; 45: 1327–1335.

[25] Peng G, Tsukamoto S, Okumura K, Ogawa H, Ikeda S, Niyonsaba F. A pancancer analysis of the oncogenic role of S100 calcium binding protein A7 (S100A7) in human tumors. Biology. 2022; 11: 284.

[26] Muoio MG, Talia M, Lappano R, Sims AH, Vella V, Cirillo F, et al. Activation of the S100A7/RAGE pathway by IGF-1 contributes to angiogenesis in breast cancer. Cancers. 2021; 13: 621.

[27] Mishra S, Charan M, Shukla RK, Agarwal P, Misri S, Verma AK, et al. cPLA2 blockade attenuates S100A7-mediated breast tumorigenicity by inhibiting the immunosuppressive tumor microenvironment. Journal of Experimental & Clinical Cancer Research. 2022; 41: 54.

[28] Anjum J, Mitra S, Das R, Alam R, Mojumder A, Emran TB, et al. A renewed concept on the MAPK signaling pathway in cancers: polyphenols as a choice of therapeutics. Pharmacological Research. 2022; 184: 106398.

[29] Bora G, Yaba A. The role of mitogen-activated protein kinase signaling pathway in endometriosis. Journal of Obstetrics and Gynaecology Research. 2021; 47: 1610–1623.

[30] Jin X, Jin W, Li G, Zheng J. Zeaxanthin attenuates OVA-induced allergic asthma in mice by regulating the p38 MAPK/β-catenin signaling pathway. Allergologia Et Immunopathologia. 2022; 50: 75–83.

[31] Wang Y, Pan L. Knockdown of CXCL3-inhibited apoptosis and inflammation in lipopolysaccharide-treated BEAS-2B and HPAEC through inactivating MAPKs pathway. Allergologia Et Immunopathologia. 2022; 50: 10–16.

[32] Liu Y, Ding Y, Nie Y, Yang M. EMP1 promotes the proliferation and invasion of ovarian cancer cells through activating the MAPK pathway. Oncotargets and Therapy. 2020; 13: 2047–2055.

[33] Song M, Zhou B, Li B, Tian L. PMEPA1 stimulates the proliferation, colony formation of pancreatic cancer cells via the mapk signaling pathway. The American Journal of the Medical Sciences. 2021; 362: 291–296.

[34] Jiang QG, Xiong CF, Lv YX. Kin17 facilitates thyroid cancer cell proliferation, migration, and invasion by activating p38 MAPK signaling pathway. Molecular and Cellular Biochemistry. 2021; 476: 727–739.

[35] Zhang XJ, Qi GT, Zhang XM, Wang L, Li FF. lncRNA RHPN1-AS1 promotes the progression of endometrial cancer through the activation of ERK/MAPK pathway. The Journal of Obstetrics and Gynaecology Research. 2021; 47: 533–543.

[36] Guo JL, Tang T, Li JH, Yang YH, Zhang L, Quan Y. LncRNA HEIH enhances paclitaxel-tolerance of endometrial cancer cells via activation of MAPK signaling pathway. Pathology Oncology Research. 2020; 26: 1757–1766.