Abstract
Background: Uterine Corpus Endometrial Carcinoma (UCEC) is a common malignancy of the female genital tract. The sine oculis homeobox homolog 1 (SIX1) protein has been documented to be important for tumor progression. However, little is known about the relationship between SIX1 and the pathogenesis of UCEC.
Objective: This study aimed to assess the prognostic value of biomarker SIX1 in UCEC by analyzing clinical traits, immune infiltration, and gene set enrichment analysis.
Methods: The Wilcoxon signed-rank test and logistic regression were used to analyze the relationship between clinicopathological characteristics and SIX1. The Kaplan-Meier method was used to assess the relationship between clinicopathological characteristics and prognosis verified by immunohistochemistry (IHC). Then gene set enrichment analysis (GSEA) was performed to explore signaling pathways correlated with SIX1 expression in UCEC. Finally, the TIMER2 database was used to analyze the correlation between SIX1 and immune infiltration, and the effect of SIX1 expression on immune cells was calculated with the CIBERSORT algorithm.
Results: We found that the expression of SIX1 in UCEC was up-regulated and correlated with a poor prognosis. Analysis showed that the expression of SIX1 was related to various clinical features and was an independent prognostic factor of UCEC. Enrichment analysis showed that SIX1 promoted the occurrence and development of UCEC by regulating multiple signaling pathways. The results of immune infiltration analysis showed that SIX1 has a complex correlation with immune infiltration.
Conclusion: Our findings indicate that SIX1 is a promising biomarker for predicting the prognosis of UCEC and is a potential therapeutic target.
Keywords: SIX1, prognostic, UCEC, immune infiltration, survival, GSEA, IHC.
Graphical Abstract
[1]
Sponholtz, T.R.; Palmer, J.R.; Rosenberg, L.; Hatch, E.E.; Adams-Campbell, L.L.; Wise, L.A. Reproductive factors and incidence of endometrial cancer in U.S. black women. Cancer Causes Control, 2017, 28(6), 579-588.
[http://dx.doi.org/10.1007/s10552-017-0880-4] [PMID: 28361447]
[http://dx.doi.org/10.1007/s10552-017-0880-4] [PMID: 28361447]
[2]
English, D.P.; Huang, M. Highlights from the society of gynecologic oncology’s 50th annual meeting on women’s cancer. Gynecol. Oncol., 2019, 153(3), 467-470.
[http://dx.doi.org/10.1016/j.ygyno.2019.04.652] [PMID: 31023555]
[http://dx.doi.org/10.1016/j.ygyno.2019.04.652] [PMID: 31023555]
[3]
Aune, D.; Rosenblatt, N.D.A.; Chan, D.S.M.; Vingeliene, S.; Abar, L.; Vieira, A.R.; Greenwood, D.C.; Bandera, E.V.; Norat, T. Anthropometric factors and endometrial cancer risk: A systematic review and dose-response meta-analysis of prospective studies. Ann. Oncol., 2015, 26(8), 1635-1648.
[http://dx.doi.org/10.1093/annonc/mdv142] [PMID: 25791635]
[http://dx.doi.org/10.1093/annonc/mdv142] [PMID: 25791635]
[4]
McCarroll, M.L.; Armbruster, S.; Pohle-Krauza, R.J.; Lyzen, A.M.; Min, S.; Nash, D.W.; Roulette, G.D.; Andrews, S.J.; von Gruenigen, V.E. Feasibility of a lifestyle intervention for overweight/obese endometrial and breast cancer survivors using an interactive mobile application. Gynecol. Oncol., 2015, 137(3), 508-515.
[http://dx.doi.org/10.1016/j.ygyno.2014.12.025] [PMID: 25681782]
[http://dx.doi.org/10.1016/j.ygyno.2014.12.025] [PMID: 25681782]
[5]
Busch, E.L.; Crous-Bou, M.; Prescott, J.; Chen, M.M.; Downing, M.J.; Rosner, B.A.; Mutter, G.L.; De Vivo, I. Endometrial cancer risk factors, hormone receptors, and mortality prediction. Cancer Epidemiol. Biomarkers Prev., 2017, 26(5), 727-735.
[http://dx.doi.org/10.1158/1055-9965.EPI-16-0821] [PMID: 28052940]
[http://dx.doi.org/10.1158/1055-9965.EPI-16-0821] [PMID: 28052940]
[6]
Coletta, R.D.; Jedlicka, P.; Gutierrez-Hartmann, A.; Ford, H.L. Transcriptional control of the cell cycle in mammary gland development and tumorigenesis. J. Mammary Gland Biol. Neoplasia, 2004, 9(1), 39-53.
[http://dx.doi.org/10.1023/B:JOMG.0000023587.40966.f6] [PMID: 15082917]
[http://dx.doi.org/10.1023/B:JOMG.0000023587.40966.f6] [PMID: 15082917]
[7]
Ng, K.T.; Man, K.; Sun, C.K.; Lee, T.K.; Poon, R.T.; Lo, C.M.; Fan, S.T. Clinicopathological significance of homeoprotein Six1 in hepatocellular carcinoma. Br. J. Cancer, 2006, 95(8), 1050-1055.
[http://dx.doi.org/10.1038/sj.bjc.6603399] [PMID: 17008870]
[http://dx.doi.org/10.1038/sj.bjc.6603399] [PMID: 17008870]
[8]
Behbakht, K.; Qamar, L.; Aldridge, C.S.; Coletta, R.D.; Davidson, S.A.; Thorburn, A.; Ford, H.L. Six1 overexpression in ovarian carcinoma causes resistance to TRAIL-mediated apoptosis and is associated with poor survival. Cancer Res., 2007, 67(7), 3036-3042.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-3755] [PMID: 17409410]
[http://dx.doi.org/10.1158/0008-5472.CAN-06-3755] [PMID: 17409410]
[9]
Li, Z.; Tian, T.; Lv, F.; Chang, Y.; Wang, X.; Zhang, L.; Li, X.; Li, L.; Ma, W.; Wu, J.; Zhang, M. Six1 promotes proliferation of pancreatic cancer cells via upregulation of cyclin D1 expression. PLoS One, 2013, 8(3), e59203.
[http://dx.doi.org/10.1371/journal.pone.0059203] [PMID: 23527134]
[http://dx.doi.org/10.1371/journal.pone.0059203] [PMID: 23527134]
[10]
Mimae, T.; Okada, M.; Hagiyama, M.; Miyata, Y.; Tsutani, Y.; Inoue, T.; Murakami, Y.; Ito, A. Upregulation of notch2 and six1 is associated with progression of early-stage lung adenocarcinoma and a more aggressive phenotype at advanced stages. Clin. Cancer Res., 2012, 18(4), 945-955.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-1946] [PMID: 22190591]
[http://dx.doi.org/10.1158/1078-0432.CCR-11-1946] [PMID: 22190591]
[11]
Ruf, R.G.; Xu, P.X.; Silvius, D.; Otto, E.A.; Beekmann, F.; Muerb, U.T.; Kumar, S.; Neuhaus, T.J.; Kemper, M.J.; Raymond, R.M., Jr; Brophy, P.D.; Berkman, J.; Gattas, M.; Hyland, V.; Ruf, E.M.; Schwartz, C.; Chang, E.H.; Smith, R.J.H.; Stratakis, C.A.; Weil, D.; Petit, C.; Hildebrandt, F. SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. Proc. Natl. Acad. Sci. USA, 2004, 101(21), 8090-8095.
[http://dx.doi.org/10.1073/pnas.0308475101] [PMID: 15141091]
[http://dx.doi.org/10.1073/pnas.0308475101] [PMID: 15141091]
[12]
Wiggs, J.L.; Yaspan, B.L.; Hauser, M.A.; Kang, J.H.; Allingham, R.R.; Olson, L.M.; Abdrabou, W.; Fan, B.J.; Wang, D.Y.; Brodeur, W.; Budenz, D.L.; Caprioli, J.; Crenshaw, A.; Crooks, K.; Delbono, E.; Doheny, K.F.; Friedman, D.S.; Gaasterland, D.; Gaasterland, T.; Laurie, C.; Lee, R.K.; Lichter, P.R.; Loomis, S.; Liu, Y.; Medeiros, F.A.; McCarty, C.; Mirel, D.; Moroi, S.E.; Musch, D.C.; Realini, A.; Rozsa, F.W.; Schuman, J.S.; Scott, K.; Singh, K.; Stein, J.D.; Trager, E.H.; Vanveldhuisen, P.; Vollrath, D.; Wollstein, G.; Yoneyama, S.; Zhang, K.; Weinreb, R.N.; Ernst, J.; Kellis, M.; Masuda, T.; Zack, D.; Richards, J.E.; Pericak-Vance, M.; Pasquale, L.R.; Haines, J.L. Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genet., 2012, 8(4), e1002654.
[http://dx.doi.org/10.1371/journal.pgen.1002654] [PMID: 22570617]
[http://dx.doi.org/10.1371/journal.pgen.1002654] [PMID: 22570617]
[13]
Cheng, W.; Li, M.; Cai, J.; Wang, K.; Zhang, C.; Bao, Z.; Liu, Y.; Wu, A. HDAC4, a prognostic and chromosomal instability marker, refines the predictive value of MGMT promoter methylation. J. Neurooncol., 2015, 122(2), 303-312.
[http://dx.doi.org/10.1007/s11060-014-1709-6] [PMID: 25557107]
[http://dx.doi.org/10.1007/s11060-014-1709-6] [PMID: 25557107]
[14]
Subramanian, A.; Tamayo, P.; Mootha, V.K.; Mukherjee, S.; Ebert, B.L.; Gillette, M.A.; Paulovich, A.; Pomeroy, S.L.; Golub, T.R.; Lander, E.S.; Mesirov, J.P. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA, 2005, 102(43), 15545-15550.
[http://dx.doi.org/10.1073/pnas.0506580102] [PMID: 16199517]
[http://dx.doi.org/10.1073/pnas.0506580102] [PMID: 16199517]
[15]
Thomas, M.A.; Yang, L.; Carter, B.J.; Klaper, R.D. Gene set enrichment analysis of microarray data from Pimephales promelas (Rafinesque), a non-mammalian model organism. BMC Genomics, 2011, 12(1), 66.
[http://dx.doi.org/10.1186/1471-2164-12-66] [PMID: 21269471]
[http://dx.doi.org/10.1186/1471-2164-12-66] [PMID: 21269471]
[16]
Taiwen, L.; Jingxin, F.; Zexian, Z.; David, C.; Jing, L.; Qianming, C.; Bo, L.; Shirley, L.X. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res., 2020, (W1), W1.
[PMID: 32589733]
[PMID: 32589733]
[18]
Gentles, A.J.; Newman, A.M.; Liu, C.L.; Bratman, S.V.; Feng, W.; Kim, D.; Nair, V.S.; Xu, Y.; Khuong, A.; Hoang, C.D. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med., 2015, 21, 938-945.
[http://dx.doi.org/10.1038/nm.3909]
[http://dx.doi.org/10.1038/nm.3909]
[19]
Azimi, F.; Scolyer, R.A.; Rumcheva, P.; Moncrieff, M.; Murali, R.; McCarthy, S.W.; Saw, R.P.; Thompson, J.F. Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J. Clin. Oncol., 2012, 30(21), 2678-2683.
[http://dx.doi.org/10.1200/JCO.2011.37.8539] [PMID: 22711850]
[http://dx.doi.org/10.1200/JCO.2011.37.8539] [PMID: 22711850]
[20]
Roy, D.; Sheng, G.Y.; Herve, S.; Carvalho, E.; Mahanty, A.; Yuan, S.; Sun, L. Interplay between cancer cell cycle and metabolism: Challenges, targets and therapeutic opportunities. Biomed. Pharmacother., 2017, 89, 288-296.
[http://dx.doi.org/10.1016/j.biopha.2017.01.019] [PMID: 28235690]
[http://dx.doi.org/10.1016/j.biopha.2017.01.019] [PMID: 28235690]
[21]
Olson, K.A.; Schell, J.C.; Rutter, J. Pyruvate and metabolic flexibility: Illuminating a path toward selective cancer therapies. Trends Biochem. Sci., 2016, 41(3), 219-230.
[http://dx.doi.org/10.1016/j.tibs.2016.01.002] [PMID: 26873641]
[http://dx.doi.org/10.1016/j.tibs.2016.01.002] [PMID: 26873641]
[22]
Martinez-Forero, I.; Rouzaut, A.; Palazon, A.; Dubrot, J.; Melero, I. Lysine 63 polyubiquitination in immunotherapy and in cancer-promoting inflammation. Clin. Cancer Res., 2009, 15(22), 6751-6757.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-1225] [PMID: 19887490]
[http://dx.doi.org/10.1158/1078-0432.CCR-09-1225] [PMID: 19887490]
[23]
Lu, P.; Wang, Y.; Liu, X.; Wang, H.; Zhang, X.; Wang, K.; Wang, Q.; Hu, R. Malignant gliomas induce and exploit astrocytic mesenchymal-like transition by activating canonical Wnt/β-catenin signaling. Med. Oncol., 2016, 33(7), 66.
[http://dx.doi.org/10.1007/s12032-016-0778-0] [PMID: 27236327]
[http://dx.doi.org/10.1007/s12032-016-0778-0] [PMID: 27236327]
[24]
Walsh, S.H.; Rosenquist, R. Immunoglobulin gene analysis of mature B-cell malignancies: Reconsideration of cellular origin and potential antigen involvement in pathogenesis. Med. Oncol., 2005, 22(4), 327-341.
[http://dx.doi.org/10.1385/MO:22:4:327] [PMID: 16260850]
[http://dx.doi.org/10.1385/MO:22:4:327] [PMID: 16260850]
[25]
Montfort, A.; Pearce, O.; Maniati, E.; Vincent, B.G.; Bixby, L.; Böhm, S.; Dowe, T.; Wilkes, E.H.; Chakravarty, P.; Thompson, R.; Topping, J.; Cutillas, P.R.; Lockley, M.; Serody, J.S.; Capasso, M.; Balkwill, F.R. A strong B-cell response is part of the immune landscape in human high-grade serous ovarian metastases. Clin. Cancer Res., 2017, 23(1), 250-262.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-0081] [PMID: 27354470]
[http://dx.doi.org/10.1158/1078-0432.CCR-16-0081] [PMID: 27354470]
[26]
Wang, J.Z.; Zhang, Y.H.; Guo, X.H.; Zhang, H.Y.; Zhang, Y. The double-edge role of B cells in mediating antitumor T-cell immunity: Pharmacological strategies for cancer immunotherapy. Int. Immunopharmacol., 2016, 36, 73-85.
[http://dx.doi.org/10.1016/j.intimp.2016.04.018] [PMID: 27111515]
[http://dx.doi.org/10.1016/j.intimp.2016.04.018] [PMID: 27111515]
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