Abstract
This study aimed to explore the expressions of signal transducer and activator of transcription 3 (STAT3) and a gene associated with retinoid-interferon induced mortality (Grim19) in epithelial ovarian cancer (EOC), and to determine their correlations with tumor progression and metastasis as well as the related mechanism. Ovarian tissue specimens resected through operation in our hospital were collected, and the correlations of Grim19 and STAT3 expressions with clinicopathological indexes were detected via immunohistochemistry (IHC) and Western blotting. Their positions in cells were observed through immunofluorescence. IHC assay results showed that STAT3 had the lowest expression level in the normal ovary, followed by those in benign ovarian tumor and borderline ovarian tumor (BOT), but it had high expression in EOC; The expression level of Grim19 was the lowest in EOC, followed by those in BOT and benign ovarian tumor successively, while it was highly expressed in the normal ovary; The expressions of STAT3 and Grim19 presented negative correlations in all kinds of ovarian tissues (p < 0.05). The expression level of STAT3 in EOC had no obvious correlations with FIGO staging or WHO classification (p > 0.05). The expression level of Grim19 in EOC in stage FIGO III–IV was higher than that in stage FIGO I–II (p < 0.05), Grim19 expression was not obviously associated with WHO classification (p > 0.05). The expressions of Grim19 and STAT3 in lymphatic metastasis lesion had significantly positive correlations with the primary lesion (p < 0.05). The Western blotting assay results were identical with the IHC results. The immunofluorescence demonstrated that STAT3 and Grim19 were mainly localized in the cytoplasm and they were colocalized in mitochondria. In conclusion, STAT3 presents high expression in EOC tissues while Grim19 is expressed in EOC tissues at a low level, which may be related to its interaction with STAT3 as well as progression, metastasis and poor prognosis of ovarian cancer.
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References
Banerjee K, Resat H (2016) Constitutive activation of STAT3 in breast cancer cells: a review. Int J Cancer 138:2570–2578
Caetano MS, Hassane M, Van HT, Bugarin E, Cumpian AM, McDowell CL, Cavazos CG, Zhang H, Deng S, Diao L, Wang J, Evans SE, Behrens C, Wistuba II, Fuqua SAW, Lin H, Stabile LP, Watowich SS, Kadara H, Moghaddam SJ (2018) Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer. Nat Commun 9:4589
Chang N, Ahn SH, Kong DS, Lee HW, Nam DH (2017) The role of STAT3 in glioblastoma progression through dual influences on tumor cells and the immune microenvironment. Mol Cell Endocrinol 451:53–65
Christie EL, Bowtell DDL (2017) Acquired chemotherapy resistance in ovarian cancer. Ann Oncol, 28: viii13-viii15
Ghirardi V, Moruzzi MC, Bizzarri N, Vargiu V, D'Indinosante M, Garganese G, Pasciuto T, Loverro M, Scambia G, Fagotti A (2020) Minimal residual disease at primary debulking surgery versus complete tumor resection at interval debulking surgery in advanced epithelial ovarian cancer: a survival analysis. Gynecol Oncol 157:209–213
Han Y, Wu J, Yang W, Wang D, Zhang T, Cheng M (2019) New STAT3-FOXL2 pathway and its function in cancer cells. BMC Mol Cell Biol 20:17
Himoto Y, Cybulska P, Shitano F, Sala E, Zheng J, Capanu M, Nougaret S, Nikolovski I, Vargas HA, Wang W, Mueller JJ, Chi DS, Lakhman Y (2019) Does the method of primary treatment affect the pattern of first recurrence in high-grade serous ovarian cancer? Gynecol Oncol 155:192–200
Hu H, Nan J, Sun Y, Zhu D, Xiao C, Wang Y, Zhu L, Wu Y, Zhao J, Wu R, Chen J, Yu H, Hu X, Zhu W, Wang J (2017) Electron leak from NDUFA13 within mitochondrial complex I attenuates ischemia-reperfusion injury via dimerized STAT3. Proc Natl Acad Sci USA 114:11908–11913
Huang Q, Zhong Y, Dong H, Zheng Q, Shi S, Zhu K, Qu X, Hu W, Zhang X, Wang Y (2020) Revisiting signal transducer and activator of transcription 3 (STAT3) as an anticancer target and its inhibitor discovery: where are we and where should we go? Eur J Med Chem 187:111922
Johnson DE, O'Keefe RA, Grandis JR (2018) Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol 15:234–248
Lheureux S, Braunstein M, Oza AM (2019a) Epithelial ovarian cancer: evolution of management in the era of precision medicine. CA Cancer J Clin 69:280–304
Lheureux S, Gourley C, Vergote I, Oza AM (2019b) Epithelial ovarian cancer. Lancet 393:1240–1253
Li F, Qi J, Qin C, Fu Z, Ren W (2018) Taurolidine promotes cell apoptosis by enhancing GRIM19 expression in liver cancer. Oncol Rep 40:3743–3751
Li H, Qian Y, Wang X, Pi R, Zhao X, Wei X (2020) Targeted activation of Stat3 in combination with paclitaxel results in increased apoptosis in epithelial ovarian cancer cells and a reduced tumour burden. Cell Prolif 53:e12719
Lin H, Lin T, Lin J, Yang M, Shen Z, Liu H, Zou Z, Zheng Z (2019) Inhibition of miR-423-5p suppressed prostate cancer through targeting GRIM-19. Gene 688:93–97
Loh CY, Arya A, Naema AF, Wong WF, Sethi G, Looi CY (2019) Signal transducer and activator of transcription (STATs) proteins in cancer and inflammation: functions and therapeutic implication. Front Oncol 9:48
Ni F, Yan CY, Zhou S, Hui PY, Du YH, Zheng L, Yu J, Hu XJ, Zhang ZG (2018) Repression of GRIM19 expression potentiates cisplatin chemoresistance in advanced bladder cancer cells via disrupting ubiquitination-mediated Bcl-xL degradation. Cancer Chemother Pharmacol 82:593–605
Peng Z, Zhang C, Zhou W, Wu C, Zhang Y (2018) The STAT3/NFIL3 signaling axis-mediated chemotherapy resistance is reversed by Raddeanin A via inducing apoptosis in choriocarcinoma cells. J Cell Physiol 233:5370–5382
Pustylnikov S, Costabile F, Beghi S, Facciabene A (2018) Targeting mitochondria in cancer: current concepts and immunotherapy approaches. Transl Res 202:35–51
Rincon M, Pereira FV (2018) A new perspective: mitochondrial Stat3 as a regulator for lymphocyte function. Int J Mol Sci 19:E1656
Tammineni P, Anugula C, Mohammed F, Anjaneyulu M, Larner AC, Sepuri NB (2013) The import of the transcription factor STAT3 into mitochondria depends on GRIM-19, a component of the electron transport chain. J Biol Chem 288:4723–4732
Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, Gaudet MM, Jemal A, Siegel RL (2018) Ovarian cancer statistics, 2018. CA Cancer J Clin 68:284–296
Verhoeven Y, Tilborghs S, Jacobs J, De Waele J, Quatannens D, Deben C, Prenen H, Pauwels P, Trinh XB, Wouters A, Smits ELJ, Lardon F, van Dam PA (2020) The potential and controversy of targeting STAT family members in cancer. Semin Cancer Biol 60:41–56
Wen W, Lowe G, Roberts CM, Finlay J, Han ES, Glackin CA, Dellinger TH (2018) Pterostilbene suppresses ovarian cancer growth via induction of apoptosis and blockade of cell cycle progression involving inhibition of the STAT3 pathway. Int J Mol Sci 19:E1983
Wu N, Hui H, Cui L, Yang F (2017) GRIM-19 represses the proliferation and invasion of cutaneous squamous cell carcinoma cells associated with downregulation of STAT3 signaling. Biomed Pharmacother 95:1169–1176
Yu H, Lee H, Herrmann A, Buettner R, Jove R (2014) Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 14:736–746
Zhang ZH, Li MY, Wang Z, Zuo HX, Wang JY, Xing Y, Jin C, Xu G, Piao L, Piao H, Ma J, Jin X (2020) Convallatoxin promotes apoptosis and inhibits proliferation and angiogenesis through crosstalk between JAK2/STAT3 (T705) and mTOR/STAT3 (S727) signaling pathways in colorectal cancer. Phytomedicine 68:153172
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ZY designed, analyzed the experiments and wrote the manuscript. YW performed the experiments and co-wrote the manuscript. YY and MY analyzed some experiment data and co-wrote the manuscript.
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The protocol of all procedures had been approved by the Ethics Committee of Guangxi Medical University Affiliated Tumor Hospital.
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Wang, Y., Yan, Y., Yang, M. et al. Expressions and clinical significances of STAT3 and Grim19 in epithelial ovarian cancer. 3 Biotech 10, 246 (2020). https://doi.org/10.1007/s13205-020-02237-x
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DOI: https://doi.org/10.1007/s13205-020-02237-x