Login Register Cart 0
Generic placeholder image

Current Protein & Peptide Science

Editor-in-Chief

ISSN (Print): 1389-2037
ISSN (Online): 1875-5550

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

T-Box Transcription Factor 2 Enhances Chemoresistance of Endometrial Cancer by Mediating NRF2 Expression

Author(s): Ning Ding, Ting Zhang, Xiaohui Yu and Shichao Zhuang*

Volume 23, Issue 8, 2022

Published on: 09 September, 2022

Page: [563 - 570] Pages: 8

DOI: 10.2174/1389203723666220823152239

Price: $65

Abstract

Background: The roles of T-Box transcription factor (TBX2) in endometrial cancer are still not clear. This study was designed to explore the roles of TBX2 in endometrial cancer and the underlying mechanisms.

Methods: The knockdown and overexpression of TBX2 in endometrial cancer cell lines were constructed by using lentivirus transduction. The xenograft animal model was established by using stable endometrial cancer cell lines. Cell viability was determined by the CCK-8 assay. The mRNA and protein levels of target genes were determined by using qPCR and Western blotting, respectively. ChIP assay was used to determine the interactions between TBX2 and nuclear factor erythroid 2-related factor 2 (NRF2).

Results: The upregulation of TBX2 was observed in endometrial cancer tissues from patients with Cisplatin- resistance and Cisplatin-resistant cells. Interestingly, TBX2 regulated cell viability and Cisplatin resistance of endometrial cancer cells. In addition, the regulatory effects of TBX2 on chemo-resistance of endometrial cancer cells were associated with the NRF2 signaling pathways. Consistently, the endometrial cancer xenograft animal model revealed that TBX2 regulated tumor growth and Cisplatin resistance, and its regulatory effects were in part by the regulation of NRF2 signaling pathways.

Conclusion: TBX 2 enhanced Cisplatin resistance of endometrial cancer by regulating the NRF2 signaling pathways.

Keywords: Endometrial cancer, chemo-resistance, cisplatin resistance, NRF2, TBX2, mRNA.

« Previous
Graphical Abstract

[1]
Morice, P.; Leary, A.; Creutzberg, C.; Abu-Rustum, N.; Darai, E. Endometrial cancer. Lancet, 2016, 387(10023), 1094-1108.
[http://dx.doi.org/10.1016/S0140-6736(15)00130-0] [PMID: 26354523]
[2]
Choi, S.; Hsu, I-C.J. Endometrial cancer. In: Handbook of Evidence-Based Radiation Oncology; Springer, 2018; pp. 653-677.
[http://dx.doi.org/10.1007/978-3-319-62642-0_30]
[3]
Gu, B.; Shang, X.; Yan, M.; Li, X.; Wang, W.; Wang, Q.; Zhang, C. Variations in incidence and mortality rates of endometrial cancer at the global, regional, and national levels, 1990–2019. Gynecol. Oncol., 2021, 161(2), 573-580.
[http://dx.doi.org/10.1016/j.ygyno.2021.01.036] [PMID: 33551200]
[4]
Bakkum-Gamez, J.N.; Gonzalez-Bosquet, J.; Laack, N.N.; Mariani, A.; Dowdy, S.C. Current issues in the management of endometrial cancer. In: Mayo Clinic Proceedings; Elsevier, 2008; Vol. 1, pp. 97-112.
[http://dx.doi.org/10.4065/83.1.97]
[5]
Burke, W.M.; Orr, J.; Leitao, M.; Salom, E.; Gehrig, P.; Olawaiye, A.B.; Brewer, M.; Boruta, D.; Herzog, T.J.; Shahin, F.A. Endometrial cancer: A review and current management strategies: Part II. Gynecol. Oncol., 2014, 134(2), 393-402.
[http://dx.doi.org/10.1016/j.ygyno.2014.06.003] [PMID: 24929052]
[6]
Cella, D.; Huang, H.; Homesley, H.D.; Montag, A.; Salani, R.; De Geest, K.; Lee, R.; Spirtos, N.M. Patient-reported peripheral neuropathy of doxorubicin and cisplatin with and without paclitaxel in the treatment of advanced endometrial cancer: Results from GOG 184. Gynecol. Oncol., 2010, 119(3), 538-542.
[http://dx.doi.org/10.1016/j.ygyno.2010.08.022] [PMID: 20863554]
[7]
Brown, J.; Smith, J.A.; Ramondetta, L.M.; Sood, A.K.; Ramirez, P.T.; Coleman, R.L.; Levenback, C.F.; Munsell, M.F.; Jung, M.; Wolf, J.K. Combination of gemcitabine and cisplatin is highly active in women with endometrial carcinoma. Cancer, 2010, 116(21), 4973-4979.
[http://dx.doi.org/10.1002/cncr.25498] [PMID: 20665499]
[8]
Dasari, S.; Bernard Tchounwou, P. Cisplatin in cancer therapy: Molecular mechanisms of action. Eur. J. Pharmacol., 2014, 740, 364-378.
[http://dx.doi.org/10.1016/j.ejphar.2014.07.025] [PMID: 25058905]
[9]
Bae-Jump, V.L.; Zhou, C.; Boggess, J.F.; Gehrig, P.A. Synergistic effect of rapamycin and cisplatin in endometrial cancer cells. Cancer, 2009, 115(17), 3887-3896.
[http://dx.doi.org/10.1002/cncr.24431] [PMID: 19484784]
[10]
Susumu, N.; Sagae, S.; Udagawa, Y.; Niwa, K.; Kuramoto, H.; Satoh, S.; Kudo, R. Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: A Japanese Gynecologic Oncolo-gy Group study. Gynecol. Oncol., 2008, 108(1), 226-233.
[http://dx.doi.org/10.1016/j.ygyno.2007.09.029] [PMID: 17996926]
[11]
Modesitt, S.; Tian, C.; Kryscio, R.; Thigpen, J.; Randall, M.; Gallion, H.; Fleming, G. Impact of body mass index on treatment outcomes in endometrial cancer patients receiving doxorubicin and cisplatin: A gynecologic oncology group study. Gynecol. Oncol., 2007, 105(1), 59-65.
[http://dx.doi.org/10.1016/j.ygyno.2006.10.045] [PMID: 17150247]
[12]
McMeekin, D.S.; Filiaci, V.L.; Thigpen, J.T.; Gallion, H.H.; Fleming, G.F.; Rodgers, W.H. The relationship between histology and outcome in advanced and recurrent endometrial cancer patients participating in first-line chemotherapy trials: A Gynecologic Oncology Group study. Gynecol. Oncol., 2007, 106(1), 16-22.
[http://dx.doi.org/10.1016/j.ygyno.2007.04.032] [PMID: 17574073]
[13]
Chitcholtan, K.; Sykes, P.H.; Evans, J.J. The resistance of intracellular mediators to doxorubicin and cisplatin are distinct in 3D and 2D endometrial cancer. J. Transl. Med., 2012, 10(1), 38.
[http://dx.doi.org/10.1186/1479-5876-10-38] [PMID: 22394685]
[14]
Chaudhry, P.; Asselin, E. Resistance to chemotherapy and hormone therapy in endometrial cancer. Endocr. Relat. Cancer, 2009, 16(2), 363-380.
[http://dx.doi.org/10.1677/ERC-08-0266] [PMID: 19190080]
[15]
Harrelson, Z.; Kelly, R.G.; Goldin, S.N.; Gibson-Brown, J.J.; Bollag, R.J.; Silver, L.M.; Papaioannou, V.E. Tbx2 is essential for patterning the atrioventricular canal and for morphogenesis of the outflow tract during heart development. Development, 2004, 131(20), 5041-5052.
[16]
Douglas, N.C.; Papaioannou, V.E. The T-box transcription factors TBX2 and TBX3 in mammary gland development and breast cancer. J. Mammary Gland Biol. Neoplasia, 2013, 18(2), 143-147.
[http://dx.doi.org/10.1007/s10911-013-9282-8] [PMID: 23624936]
[17]
Abrahams, A.; Parker, M.I.; Prince, S. The T-box transcription factor Tbx2: Its role in development and possible implication in cancer. IUBMB Life, 2010, 62(2), 92-102.
[PMID: 19960541]
[18]
Nandana, S.; Tripathi, M.; Duan, P.; Chu, C.Y.; Mishra, R.; Liu, C.; Jin, R.; Yamashita, H.; Zayzafoon, M.; Bhowmick, N.A.; Zhau, H.E.; Matusik, R.J.; Chung, L.W.K. Bone metastasis of prostate cancer can be therapeutically targeted at the TBX2–WNT signaling axis. Cancer Res., 2017, 77(6), 1331-1344.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-0497] [PMID: 28108510]
[19]
Tasaka, R.; Fukuda, T.; Shimomura, M.; Inoue, Y.; Wada, T.; Kawanishi, M.; Yasui, T.; Sumi, T. TBX2 expression is associated with platinum-sensitivity of ovarian serous carcinoma. Oncol. Lett., 2018, 15(3), 3085-3090.
[PMID: 29435041]
[20]
You, J.; Li, J.; Ke, C.; Xiao, Y.; Lu, C.; Huang, F.; Mi, Y.; Xia, R.; Li, Q. Oncogenic long intervening noncoding RNA Linc00284 promotes c-Met expression by sponging miR-27a in colorectal cancer. Oncogene, 2021, 40(24), 4151-4166.
[http://dx.doi.org/10.1038/s41388-021-01839-w] [PMID: 34050266]
[21]
Ding, N.; Zhang, H.; Su, S.; Ding, Y.; Yu, X.; Tang, Y.; Wang, Q. Liu, P Emodin enhances the chemosensitivity of endometrial cancer by in-hibiting ROS-mediated Cisplatin-resistance. Anticancer. Agents Med. Chem., 2018, 18, 1054-1063.
[22]
Galluzzi, L.; Senovilla, L.; Vitale, I.; Michels, J.; Martins, I.; Kepp, O.; Castedo, M.; Kroemer, G. Molecular mechanisms of cisplatin re-sistance. Oncogene, 2012, 31(15), 1869-1883.
[http://dx.doi.org/10.1038/onc.2011.384] [PMID: 21892204]
[23]
Wansleben, S.; Davis, E.; Peres, J.; Prince, S. A novel role for the anti-senescence factor TBX2 in DNA repair and cisplatin resistance. Cell Death Dis., 2013, 4(10), e846-e846.
[http://dx.doi.org/10.1038/cddis.2013.365] [PMID: 24113180]
[24]
Kimani, S.; Wansbelen, S.; Davis, E.; Peres, J.; Prince, S. Abstract B19: The oncogenic TBX2 activates the ATM-CHK2-p53 axis to confer cisplatin resistance in breast cancer and melanoma. In: AACR; , 2016.
[25]
Vance, K.W.; Carreira, S.; Brosch, G.; Goding, C.R. Tbx2 is overexpressed and plays an important role in maintaining proliferation and suppression of senescence in melanomas. Cancer Res., 2005, 65(6), 2260-2268.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-3045] [PMID: 15781639]
[26]
Crawford, N.T.; McIntyre, A.J.; McCormick, A.; D’Costa, Z.C.; Buckley, N.E.; Mullan, P.B. TBX2 interacts with heterochromatin protein 1 to recruit a novel repression complex to EGR1-targeted promoters to drive the proliferation of breast cancer cells. Oncogene, 2019, 38(31), 5971-5986.
[http://dx.doi.org/10.1038/s41388-019-0853-z] [PMID: 31253870]
[27]
Kaspar, J.W.; Niture, S.K.; Jaiswal, A.K. Nrf2:INrf2 (Keap1) signaling in oxidative stress. Free Radic. Biol. Med., 2009, 47(9), 1304-1309.
[http://dx.doi.org/10.1016/j.freeradbiomed.2009.07.035] [PMID: 19666107]
[28]
Niture, S.K.; Khatri, R.; Jaiswal, A.K. Regulation of Nrf2—an update. Free Radic. Biol. Med., 2014, 66, 36-44.
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.02.008] [PMID: 23434765]
[29]
Sporn, M.B.; Liby, K.T. NRF2 and cancer: The good, the bad and the importance of context. Nat. Rev. Cancer, 2012, 12(8), 564-571.
[http://dx.doi.org/10.1038/nrc3278] [PMID: 22810811]
[30]
Bao, L-J.; Jaramillo, M.C.; Zhang, Z-B.; Zheng, Y-X.; Yao, M.; Zhang, D.D.; Yi, X-F. Nrf2 induces cisplatin resistance through activation of autophagy in ovarian carcinoma. Int. J. Clin. Exp. Pathol., 2014, 7(4), 1502-1513.
[PMID: 24817946]
[31]
Wang, X.J.; Sun, Z.; Villeneuve, N.F.; Zhang, S.; Zhao, F.; Li, Y.; Chen, W.; Yi, X.; Zheng, W.; Wondrak, G.T.; Wong, P.K.; Zhang, D.D. Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis, 2008, 29(6), 1235-1243.
[http://dx.doi.org/10.1093/carcin/bgn095] [PMID: 18413364]
[32]
Roh, J.L.; Kim, E.H.; Jang, H.; Shin, D. Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to ar-tesunate-induced ferroptosis. Redox Biol., 2017, 11, 254-262.
[http://dx.doi.org/10.1016/j.redox.2016.12.010] [PMID: 28012440]

Rights & Permissions Print Cite
Article Metrics
3
© 2024 Bentham Science Publishers | Privacy Policy