Journal of Shandong University (Health Sciences) ›› 2021, Vol. 59 ›› Issue (10): 25-31.doi: 10.6040/j.issn.1671-7554.0.2021.0230

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Effects of Trametinib on PAX8 expression in ovarian cancer

WANG Zhengyang1, XIA Yan2, SHI Kaixuan3, TAO Kun4, WANG Xiaojie1,2   

  1. 1. Graduate School of Bengbu Medical College, Bengbu 233000, Anhui, China;
    2. Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China;
    3. State Key Laboratory of Oncogenes and Related Genes, Clinical Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China;
    4. Department of Pathology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200050, China
  • Published:2021-10-15

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Abstract: Objective To investigate the effects of Trametinib, a MEK inhibitor, on PAX8 expression in ovarian cancer. Methods The expression changes of related genes in ovarian cancer cells treated with Trametinib were detected with gene set enrichment analysis(GSEA). The effects of Trametinib on the protein and mRNA expressions of PAX8 in ovarian cancer cells were detected with Western blotting, immunofluorescence staining and real-time quantitative PCR. The effects of Trametinib on the proliferation of ovarian cancer cells was detected with crystal violet staining. The change of PAX8 expression and cell proliferation in KRAS mutant ovarian cancer cells transfected with si-ELK1-RNA were detected with Western blotting, real-time quantitative PCR and CCK8 experiment. Results GSEA showed that Trametinib inhibited KRAS and ELK1 genes in ovarian cancer cells(P<0.01). Real-time quantitative PCR showed that Trametinib inhibited PAX8 transcription in KRAS mutant ovarian cancer cells(P<0.001). Crystal violet staining showed that Trametinib reduced the proliferation of KRAS mutated ovarian cancer cells. Western blotting showed that Trametinib inhibited the expression of PAX8 and ELK1 genes in KRAS mutant ovarian cancer cells(P<0.001), and interference with ELK1 gene inhibited the expression of PAX8 gene in KRAS mutant ovarian cancer cells(P<0.001); The results of CCK8 showed that interfering with ELK1 gene expression inhibited the proliferation of KRAS mutant ovarian cancer cells(P<0.05). Conclusion Trametinib inhibits PAX8 expression and cell proliferation through ELK1 gene in KRAS mutant ovarian cancer.

Key words: Trametinib, Ovarian cancer, PAX8 protein, Cell proliferation, KRAS gene mutation

CLC Number: 

  • R737.31
[1] Spreafico A, Oza A, Clarke B, et al. Genotype-matched treatment for patients with advanced type I epithelial ovarian cancer[J]. Gynecologic Oncology, 2017, 5(144): 23-28.
[2] Jessmon P, Boulanger T, Zhou W, et al. Epidemiology and treatment patterns of epithelial ovarian cancer[J]. Expert Rev Anticancer Ther, 2017, 17(5): 427-437.
[3] Webb P, Jordan S. Epidemiology of epithelial ovarian cancer[J]. Best Pract Res Clin Obstet Gynaecol, 2017, 41: 3-14. doi: 10.1016/j.bpobgyn.2016.08.006.
[4] Bleu M, Mermet-Meillon F, Apfel V, et al. PAX8 and MECOM are interaction partners driving ovarian cancer[J]. Nature Communications, 2021, 12(1): 2442-2453.
[5] Chu Y, Zhu C, Wang Q, et al. Adipose-derived mesenchymal stem cells induced PAX8 promotes ovarian cancer cell growth by stabilizing TAZ protein[J]. J Cell Mol Med, 2021, 25(9): 4434-4443.
[6] Laury A, Perets R, Piao H, et al. A comprehensive analysis of PAX8 expression in human epithelial tumors[J]. Am J Surg Pathol, 2011, 35(6): 816-826.
[7] Nonaka D, Chiriboga L, Soslow RA. Expression of pax8 as a useful marker in distinguishing ovarian carcinomas from mammary carcinomas[J]. Am J Surg Pathol, 2008, 32(10): 1566-1571.
[8] Rodgers L, ÓhAinmhire E, Young A, et al. Loss of PAX8 in high-grade serous ovarian cancer reduces cell survival despite unique modes of action in the fallopian tube and ovarian surface epithelium[J]. Oncotarget, 2016, 7(22): 32785-32795.
[9] Palma T, Lucci V, Cristofaro T, et al. A role for PAX8 in the tumorigenic phenotype of ovarian cancer cells[J]. Bmc Cancer, 2014, 14: 292-230. doi: 10.1186/1471-2407-14-292.
[10] Adler E, Corona R, Lee J, et al. The PAX8 cistrome in epithelial ovarian cancer[J]. Oncotarget, 2017, 8(65): 108316-108332.
[11] Shi K, Yin X, Cai MC, et al. PAX8 regulon in human ovarian cancer links lineage dependency with epigenetic vulnerability to HDAC inhibitors[J]. eLife Sciences, 2019, 8: e44304. doi: 10.7554/eLife.44306.
[12] Gershenson D, Sun C, Wong K. Impact of mutational status on survival in low-grade serous carcinoma of the ovary or peritoneum[J]. Br J Cancer, 2015, 113(9): 1254-1258.
[13] Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma[J]. Nature, 2010, 467(7315): 596-599.
[14] Flaherty K, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma[J]. N Engl J Med, 2012, 367(2): 107-114.
[15] 金剑英, 朱延安, 谢静静, 等. MEK抑制剂在K-RAS基因突变的结直肠癌细胞中的耐药机制[J]. 浙江医学, 2020, 42(2): 109-113. JIN Jianying, ZHU Yanan, XIE Jingjing, et al. Effect of MEK inhibitor trametinib on drug resistance in K-RAS mutated colorectal cancer cells and its mechanism[J]. Zhejiang Medical Journal, 2020, 42(2): 109-113.
[16] 陈晓艳, 龚一心, 焦顺昌. 西妥昔单抗联合曲美替尼对人结肠癌细胞增殖和凋亡的影响[J]. 解放军医学院学报, 2019, 40(6): 590-595. CHEN Xiaoyan, GONG Yixin, JIAO Shunchang. Effects of cetuximab combined with trametinib on proliferation and apoptosis of human colon cancer cells[J]. Academic Journal of Chinese PLA Medical School, 2019, 40(6): 590-595.
[17] Chi N, Epstein J. Getting your Pax straight: Pax proteins in development and disease[J]. Trends Genet, 2002, 18(1): 41-47.
[18] Hibbs K, Skubitz K, Pambuccian S, et al. Differential gene expression in ovarian carcinoma: identification of potential biomarkers[J]. Am J Pathol, 2004, 165(2): 397-414.
[19] Bleu M, Gaulis S, Rui L, et al. PAX8 activates metabolic genes via enhancer elements in Renal Cell Carcinoma[J]. Nature Communications, 2019, 10(1): 1-10.
[20] Elias K, Emori M, Westerling T, et al. Epigenetic remodeling regulates transcriptional changes between ovarian cancer and benign precursors[J]. Jci Insight, 2016, 1(13): e87988. doi: 10.1172/jci.insight.87988.
[21] Belardinelli A, Barabas M, Himmelbach M, et al. Anticipatory eye fixations reveal tool knowledge for tool interaction[J]. Exp Brain Res, 2016, 234(8): 2415-2431.
[22] Hansen R, Peters U, Babbar A, et al. The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors[J]. Nat Struct Mol Biol, 2018, 25(6): 454-462.
[23] Li X, Wang J, Zhang C, et al. Circular RNA circITGA7 inhibits colorectal cancer growth and metastasis by modulating the Ras pathway and upregulating transcription of its host gene ITGA7[J]. J Pathol, 2018, 246(2): 166-179.
[24] Gong S, Xu DS, Zhu JL, et al. Efficacy of the MEK inhibitor cobimetinib and its potential application to colorectal cancer cells[J]. Cell Physiol Biochem, 2018, 47(2): 680-693.
[25] Akatsu Y, Takahashi N, Yoshimatsu Y, et al. Fibroblast growth factor signals regulate transforming growth factorβ-induced endothelial-to-myofibroblast transition of tumor endothelial cells via Elk1[J]. Mol Oncol, 2019, 13(8): 1706-1724.
[26] Ma J, Liu X, Chen H, et al. The c-KIT-ERK1/2 signaling activated ELK1 and upregulated carcinoembryonic antigen expression to promote colorectal cancer progression[J]. Cancer Science, 2021, 112(2): 655-667.
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