Abstract
By analyzing the gene expression of endometrial carcinoma (EC) patients, the key factors in PI3K signaling pathway and its related genes mediating EC were explored. The EC samples and normal endometrial samples were downloaded from TCGA database and GTEx database. The R language “limma” package was used for differential analysis, and the expression level of genes in each tissue was analyzed by “gganatogram” package. Functional enrichment analysis of differential genes was carried out by KOBAS, an online bioinformatics website. The correlation between key genes and differential genes was evaluated using TCGA data and GTEx combined gene expression data. The corresponding clinical data were downloaded from TCGA database and GTEx database, and the R language “survival” package was used to assess the potential of candidate differential genes as a key factor of EC. Based on the combined differential analysis of TCGA and GTEx databases, 299 genes with significant differential in expression were finally got. Functional enrichment analysis revealed that genes were predominantly enriched in the entry of “Pathways in cancer”, including RAC2 and PIK3R3 genes which were related with the abnormal PI3K pathway in cancer. PIK3R3, a key gene in the PI3K signaling pathway, was highly-expressed in EC. SPDEF, GCNT2, KIAA1324, C9orf152, MARVELD3, and APEX2 genes were found to be positively correlated with PIK3R3 in EC, all of which were highly expressed in EC. KM survival analysis showed that SPDEF, GCNT2, KIAA1324 and C9orf152 were significantly correlated with patients’ survival. ROC analysis showed that SPDEF, GCNT2, KIAA1324 and C9orf152 gene could be used as potential markers for prognosis and survival of EC patients. It was found that PIK3R3, a key gene in the PI3K signaling pathway, was highly expressed in EC. The SPDEF, GCNT2, KIAA1324 and C9orf152 genes were also highly expressed in EC, and were positively correlated with PIK3R3 in EC. Moreover, they are significantly correlated with the patients’ survival, suggesting that they may be potential markers for the prognosis of patients with EC.
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References
Barra F, Evangelisti G, Ferro Desideri L, Di Domenico S, Ferraioli D, Vellone VG, De Cian F, Ferrero S (2019) Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer. Expert Opin Investig Drugs 28(2):131–142. https://doi.org/10.1080/13543784.2018.1558202
Byrne FL, Martin AR, Kosasih M, Caruana BT, Farrell R (2020) The Role of Hyperglycemia in Endometrial Cancer Pathogenesis. Cancers (Basel) 12(5) https://doi.org/10.3390/cancers12051191
Campbell TM, Castro MA, Ponder BA, Meyer KB (2016) Identification of post-transcriptional modulators of breast cancer transcription factor activity using MINDy. PLoS One 11(12):e0168770. https://doi.org/10.1371/journal.pone.0168770
Chen J, Zhao KN, Li R, Shao R, Chen C (2014) Activation of PI3K/Akt/mTOR pathway and dual inhibitors of PI3K and mTOR in endometrial cancer. Curr Med Chem 21(26):3070–3080. https://doi.org/10.2174/0929867321666140414095605
Chiu HC, Li CJ, Yiang GT, Tsai AP, Wu MY (2019) Epithelial to mesenchymal transition and cell biology of molecular regulation in endometrial carcinogenesis. J Clin Med 8(4) https://doi.org/10.3390/jcm8040439
Deng L, Broaddus RR, McCampbell A, Shipley GL, Loose DS, Stancel GM, Pickar JH, Davies PJ (2005) Identification of a novel estrogen-regulated gene, EIG121, induced by hormone replacement therapy and differentially expressed in type I and type II endometrial cancer. Clin Cancer Res 11(23):8258–8264. https://doi.org/10.1158/1078-0432.CCR-05-1189
Dong L, Hui L (2016) HOTAIR promotes proliferation, migration, and invasion of ovarian cancer SKOV3 cells through regulating PIK3R3. Med Sci Monit 22:325–331. https://doi.org/10.12659/msm.894913
Dong P, Yu B, Pan L, Tian X, Liu F (2018) Identification of key genes and pathways in triple-negative breast cancer by integrated bioinformatics analysis. Biomed Res Int 2018:2760918. https://doi.org/10.1155/2018/2760918
Dork T, Hillemanns P, Tempfer C, Breu J, Fleisch MC (2020) Genetic susceptibility to endometrial cancer: Risk factors and clinical management. Cancers (Basel) 12(9) https://doi.org/10.3390/cancers12092407
Eritja N, Yeramian A, Chen BJ, Llobet-Navas D, Ortega E, Colas E, Abal M, Dolcet X, Reventos J, Matias-Guiu X (2017) Endometrial carcinoma: specific targeted pathways. Adv Exp Med Biol 943:149–207. https://doi.org/10.1007/978-3-319-43139-0_6
Ge Y, Liu H, Qiu X, Ma G, Wang H, Du M, Wang M, Zhao Q, Tao G, Chu H, Zhang Z (2018) Genetic variants in PI3K/Akt/mTOR pathway genes contribute to gastric cancer risk. Gene 670:130–135. https://doi.org/10.1016/j.gene.2018.05.093
Grunda JM, Fiveash J, Palmer CA, Cantor A, Fathallah-Shaykh HM, Nabors LB, Johnson MR (2010) Rationally designed pharmacogenomic treatment using concurrent capecitabine and radiotherapy for glioblastoma; gene expression profiles associated with outcome. Clin Cancer Res 16(10):2890–2898. https://doi.org/10.1158/1078-0432.CCR-09-3151
Heim S, Sill M, Jones DT, Vasiljevic A, Jouvet A, Fevre-Montange M, Wesseling P, Beschorner R, Mittelbronn M, Kohlhof P, Hovestadt V, Johann P, Kool M, Pajtler KW, Korshunov A, Ruland V, Sperveslage J, Thomas C, Witt H, von Deimling A, Paulus W, Pfister SM, Capper D, Hasselblatt M (2016) Papillary tumor of the pineal region: a distinct molecular entity. Brain Pathol 26(2):199–205. https://doi.org/10.1111/bpa.12282
Hu X, Han T, Bian Y, Tong H, Wen X, Li Y, Wan X (2020) Knockdown of SLCO4C1 inhibits cell proliferation and metastasis in endometrial cancer through inactivating the PI3K/Akt signaling pathway. Oncol Rep 43(3):919–929. https://doi.org/10.3892/or.2020.7478
Kang JM, Park S, Kim SJ, Kim H, Lee B, Kim J, Park J, Kim ST, Yang HK, Kim WH, Kim SJ (2015) KIAA1324 suppresses gastric cancer progression by inhibiting the oncoprotein GRP78. Cancer Res 75(15):3087–3097. https://doi.org/10.1158/0008-5472.CAN-14-3751
Kyuno D, Yamaguchi H, Ito T, Kono T, Kimura Y, Imamura M, Konno T, Hirata K, Sawada N, Kojima T (2014) Targeting tight junctions during epithelial to mesenchymal transition in human pancreatic cancer. World J Gastroenterol 20(31):10813–10824. https://doi.org/10.3748/wjg.v20.i31.10813
Lengyel CG, Altuna SC, Habeeb BS, Trapani D, Khan SZ (2019) The potential of PI3K/AKT/mTOR signaling as a druggable target for endometrial and ovarian carcinomas. Curr Drug Targets https://doi.org/10.2174/1389450120666191120123612
Leskela S, Perez-Mies B, Rosa-Rosa JM, Cristobal E, Biscuola M, Palacios-Berraquero ML, Ong S, Matias-Guiu Guia X, Palacios J (2019) Molecular basis of tumor heterogeneity in endometrial carcinosarcoma. Cancers (Basel) 11(7) https://doi.org/10.3390/cancers11070964
Liang C, Xu Y, Ge H, Xing B, Li G, Li G, Wu J (2017) miR-564 inhibits hepatocellular carcinoma cell proliferation and invasion by targeting the GRB2-ERK1/2-AKT axis. Oncotarget 8(64):107543–107557. https://doi.org/10.18632/oncotarget.22504
Meiners J, Schulz K, Moller K, Hoflmayer D, Burdelski C, Hube-Magg C, Simon R, Gobel C, Hinsch A, Reiswich V, Weidemann S, Izbicki JR, Sauter G, Jacobsen F, Moller-Koop C, Mandelkow T, Blessin NC, Lutz F, Viehweger F, Lennartz M, Fraune C, Heinzer H, Minner S, Bonk S, Huland H, Graefen M, Schlomm T, Buscheck F (2019) Upregulation of SPDEF is associated with poor prognosis in prostate cancer. Oncol Lett 18(5):5107–5118. https://doi.org/10.3892/ol.2019.10885
Mitamura T, Dong P, Ihira K, Kudo M, Watari H (2019) Molecular-targeted therapies and precision medicine for endometrial cancer. Jpn J Clin Oncol 49(2):108–120. https://doi.org/10.1093/jjco/hyy159
Nowakowska M, Matysiak-Burzynska Z, Kowalska K, Pluciennik E, Dominska K, Piastowska-Ciesielska AW (2016) Angiotensin II promotes endometrial cancer cell survival. Oncol Rep 36(2):1101–1110. https://doi.org/10.3892/or.2016.4887
Peng F, He Q, Cheng C, Pan J (2019) GCNT2 induces epithelial-mesenchymal transition and promotes migration and invasion in esophageal squamous cell carcinoma cells. Cell Biochem Funct 37(1):42–51. https://doi.org/10.1002/cbf.3371
Roncolato F, Lindemann K, Willson ML, Martyn J, Mileshkin L (2019) PI3K/AKT/mTOR inhibitors for advanced or recurrent endometrial cancer. Cochrane Database Syst Rev 10:CD012160. https://doi.org/10.1002/14651858.CD012160.pub2
Schlumbrecht MP, Xie SS, Shipley GL, Urbauer DL, Broaddus RR (2011) Molecular clustering based on ERalpha and EIG121 predicts survival in high-grade serous carcinoma of the ovary/peritoneum. Mod Pathol 24(3):453–462. https://doi.org/10.1038/modpathol.2010.211
Sudhakar N, Priya Doss CG, Thirumal Kumar D, Chakraborty C, Anand K, Suresh M (2016) Deciphering the impact of somatic mutations in exon 20 and exon 9 of PIK3CA gene in breast tumors among Indian women through molecular dynamics approach. J Biomol Struct Dyn 34(1):29–41. https://doi.org/10.1080/07391102.2015.1007483
Supernat A, Lapinska-Szumczyk S, Majewska H, Gulczynski J, Biernat W, Wydra D, Zaczek AJ (2014) A multimarker qPCR platform for the characterisation of endometrial cancer. Oncol Rep 31(2):1003–1013. https://doi.org/10.3892/or.2013.2924
Wang G, Yang X, Li C, Cao X, Luo X, Hu J (2014) PIK3R3 induces epithelial-to-mesenchymal transition and promotes metastasis in colorectal cancer. Mol Cancer Ther 13(7):1837–1847. https://doi.org/10.1158/1535-7163.MCT-14-0049
Wu J, Qin W, Wang Y, Sadik A, Liu J, Wang Y, Song P, Wang X, Sun K, Zeng J, Wang L (2018) SPDEF is overexpressed in gastric cancer and triggers cell proliferation by forming a positive regulation loop with FoxM1. J Cell Biochem 119(11):9042–9054. https://doi.org/10.1002/jcb.27161
Xu W, Yu M, Qin J, Luo Y, Zhong M (2020) LACTB regulates PIK3R3 to promote autophagy and inhibit EMT and proliferation through the PI3K/AKT/mTOR signaling pathway in colorectal cancer. Cancer Manag Res 12:5181–5200. https://doi.org/10.2147/CMAR.S250661
Zhang H, Meng F, Wu S, Kreike B, Sethi S, Chen W, Miller FR, Wu G (2011) Engagement of I-branching {beta}-1, 6-N-acetylglucosaminyltransferase 2 in breast cancer metastasis and TGF-{beta} signaling. Cancer Res 71(14):4846–4856. https://doi.org/10.1158/0008-5472.CAN-11-0414
Zhang K, Li H, Yan Y, Zang Y, Li K, Wang Y, Xue F (2019) Identification of key genes and pathways between type I and type II endometrial cancer using bioinformatics analysis. Oncol Lett 18(3):2464–2476. https://doi.org/10.3892/ol.2019.10550
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Liu, Z., Hong, Z., Ma, H. et al. Key factors mediated by PI3K signaling pathway and related genes in endometrial carcinoma. J Bioenerg Biomembr 52, 465–473 (2020). https://doi.org/10.1007/s10863-020-09854-4
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DOI: https://doi.org/10.1007/s10863-020-09854-4