Predicting recurrence in intermediate‑ and high‑risk stage IB‑IIB cervical cancer treated with adjuvant cisplatin and paclitaxel chemotherapy post‑radical hysterectomy: The role of TBX2 expression

Noda,Takuya; Fukuda,Takeshi; Uchikura,Eijiro; Awazu,Yuichiro; Wada,Takuma; Tasaka,Reiko; Yamauchi,Makoto; Yasui,Tomoyo; Sumi,Toshiyuki

doi:10.3892/ol.2024.14547

Predicting recurrence in intermediate‑ and high‑risk stage IB‑IIB cervical cancer treated with adjuvant cisplatin and paclitaxel chemotherapy post‑radical hysterectomy: The role of TBX2 expression

Authors:
- Takuya Noda
- Takeshi Fukuda
- Eijiro Uchikura
- Yuichiro Awazu
- Takuma Wada
- Reiko Tasaka
- Makoto Yamauchi
- Tomoyo Yasui
- Toshiyuki Sumi
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Affiliations: Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, Osaka 5454‑8585, Japan, Department of Obstetrics and Gynecology, Osaka Metropolitan University Graduate School of Medicine, Osaka 5454‑8585, Japan
Published online on: June 28, 2024 https://doi.org/10.3892/ol.2024.14547
Article Number: 414
Copyright: © Noda et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cervical cancer remains a significant global health concern despite advances in prevention and treatment. Current management for intermediate‑ to high‑risk stage IB‑IIB cervical cancer post‑radical hysterectomy involves irradiation or concurrent chemoradiation, although patients can exhibit several adverse events. Adjuvant chemotherapy has emerged as a promising alternative; however, its efficacy remains unclear. T‑box (TBX)2 is a transcription factor that is involved in the regulation of cell cycle progression during cancer and embryonic development. Additionally, elevated expression of TBX2 is associated with resistance to DNA‑damaging chemotherapeutic agents, such as cisplatin, carboplatin and doxorubicin. The aim of the present study was to investigate the relationship between TBX2 expression and recurrence in patients receiving adjuvant cisplatin and paclitaxel (TP) chemotherapy post‑radical hysterectomy. Additionally, the impact of TBX2 knockdown on cisplatin sensitivity was assessed in vitro. A retrospective analysis was performed on 100 patients. Patients were categorized into two groups based on recurrence within 2 years of treatment initiation: The non‑recurrent group (n=85) and the recurrent group (n=15). TBX2 expression was assessed immunohistochemically, and multiple logistic regression analysis was performed to identify predictors of recurrence. Additionally, the impact of small interfering RNA‑mediated TBX2 knockdown on cervical cancer cell sensitivity to cisplatin was evaluated. TBX2 expression was significantly higher in the recurrent group compared with that in the non‑recurrent group (P<0.01). Patients were stratified into low TBX2 expression (weighted score ≤8; n=80) and high TBX2 expression (weighted score ≥9; n=20) groups. The high TBX2 expression group exhibited a higher recurrence rate compared with the low expression group (P<0.01). Multivariate analysis identified TBX2 expression as an independent predictor of recurrence (P<0.01). Moreover, TBX2 knockdown significantly enhanced cervical cancer cell sensitivity to cisplatin in vitro (P<0.05). These findings highlight TBX2 expression as a potential predictive biomarker for recurrence amongst patients with intermediate‑ to high‑risk stage IB‑IIB cervical cancer receiving adjuvant TP chemotherapy post‑radical hysterectomy.

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1	Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I and Jemal A: Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 74:229–263. 2024. View Article : Google Scholar : PubMed/NCBI
2	FIGO Committee on Gynecologic Oncology, . FIGO staging for carcinoma of the vulva, cervix, and corpus uteri. Int J Gynaecol Obstet. 125:97–98. 2014. View Article : Google Scholar : PubMed/NCBI
3	Abu-Rustum NR, Yashar CM, Arend R, Barber E, Bradley K, Brooks R, Campos SM, Chino J, Chon HS, Crispens MA, et al: NCCN guidelines^® insights: Cervical cancer, version 1.2024. J Natl Compr Canc Netw. 21:1224–1233. 2023. View Article : Google Scholar : PubMed/NCBI
4	Ebina Y, Mikami M, Nagase S, Tabata T, Kaneuchi M, Tashiro H, Mandai M, Enomoto T, Kobayashi Y, Katabuchi H, et al: Japan society of gynecologic oncology guidelines 2017 for the treatment of uterine cervical cancer. Int J Clin Oncol. 24:1–19. 2019. View Article : Google Scholar : PubMed/NCBI
5	Peters WA III, Liu PY, Barrett RJ II, Stock RJ, Monk BJ, Berek JS, Souhami L, Grigsby P, Gordon W Jr and Alberts DS: Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol. 18:1606–1613. 2000. View Article : Google Scholar : PubMed/NCBI
6	Hosaka M, Watari H, Kato T, Odagiri T, Konno Y, Endo D, Mitamura T, Kikawa S, Suzuki Y and Sakuragi N: Clinical efficacy of paclitaxel/cisplatin as an adjuvant chemotherapy for patients with cervical cancer who underwent radical hysterectomy and systematic lymphadenectomy. J Surg Oncol. 105:612–616. 2012. View Article : Google Scholar : PubMed/NCBI
7	Matoda M, Takeshima N, Michimae H, Iwata T, Yokota H, Torii Y, Yamamoto Y, Takehara K, Nishio S, Takano H, et al: Postoperative chemotherapy for node-positive cervical cancer: Results of a multicenter phase II trial (JGOG1067). Gynecol Oncol. 149:513–519. 2018. View Article : Google Scholar : PubMed/NCBI
8	Li S, Hu T, Chen Y, Zhou H, Li X, Cheng X, Yang R, Wang S, Xie X and Ma D: Adjuvant chemotherapy, a valuable alternative option in selected patients with cervical cancer. PLoS One. 8:e738372013. View Article : Google Scholar : PubMed/NCBI
9	Weng D, Xiong H, Zhu C, Wan X, Chen Y, Wang X, Zhang Y, Jiang J, Zhang X, Gao Q, et al: Adjuvant chemotherapy versus adjuvant concurrent chemoradiotherapy after radical surgery for early-stage cervical cancer: A randomized, non-inferiority, multicenter trial. Front Med. 17:93–104. 2023. View Article : Google Scholar : PubMed/NCBI
10	Zhang H, Yu R, Zhang L, Wang R and Xiao L: Chemotherapy versus chemoradiotherapy for FIGO stages IB1 and IIA1 cervical squamous cancer patients with lymphovascular space invasion: A retrospective study. BMC Cancer. 22:2022022. View Article : Google Scholar : PubMed/NCBI
11	Chang F, Xing P, Song F, Du X, Wang G, Chen K and Yang J: The role of T-box genes in the tumorigenesis and progression of cancer. Oncol Lett. 12:4305–4311. 2016. View Article : Google Scholar : PubMed/NCBI
12	Bilican B and Goding CR: Cell cycle regulation of the T-box transcription factor tbx2. Exp Cell Res. 312:2358–2366. 2006. View Article : Google Scholar : PubMed/NCBI
13	Abrahams A, Parker MI and Prince S: The T-box transcription factor Tbx2: Its role in development and possible implication in cancer. IUBMB Life. 62:92–102. 2010. View Article : Google Scholar : PubMed/NCBI
14	Hu R, Deng J, Li C, Xu C, Cui ZH and Zhao J: Clinical significance of TBX2 in esophageal squamous cell carcinomas and its role in cell migration and invasion. Eur Rev Med Pharmacol Sci. 24:3062–3068. 2020.PubMed/NCBI
15	Ding N, Zhang T, Yu X and Zhuang S: T-box transcription factor 2 enhances chemoresistance of endometrial cancer by mediating NRF2 expression. Curr Protein Pept Sci. 23:563–570. 2022. View Article : Google Scholar : PubMed/NCBI
16	Vance KW, Carreira S, Brosch G and Goding CR: Tbx2 is overexpressed and plays an important role in maintaining proliferation and suppression of senescence in melanomas. Cancer Res. 65:2260–2268. 2005. View Article : Google Scholar : PubMed/NCBI
17	Nandana S, Tripathi M, Duan P, Chu CY, Mishra R, Liu C, Jin R, Yamashita H, Zayzafoon M, Bhowmick NA, et al: Bone metastasis of prostate cancer can be therapeutically targeted at the TBX2-WNT signaling axis. Cancer Res. 77:1331–1344. 2017. View Article : Google Scholar : PubMed/NCBI
18	Huang Y, Li Z, Zhong Q, Li G, Zhang Y and Huang Z: Association of TBX2 and P21 expression with clinicopathological features and survival of laryngeal squamous cell carcinoma. Int J Clin Exp Med. 7:5394–5402. 2014.PubMed/NCBI
19	Zhang Z and Guo Y: High TBX2 expression predicts poor prognosis in non-small cell lung cancer. Neoplasma. 61:476–480. 2014. View Article : Google Scholar : PubMed/NCBI
20	Yu H, Liu BO, Liu A, Li K and Zhao H: T-box 2 expression predicts poor prognosis in gastric cancer. Oncol Lett. 10:1689–1693. 2015. View Article : Google Scholar : PubMed/NCBI
21	Mahlamäki EH, Bärlund M, Tanner M, Gorunova L, Höglund M, Karhu R and Kallioniemi A: Frequent amplification of 8q24, 11q, 17q, and 20q-specific genes in pancreatic cancer. Genes Chromosomes Cancer. 35:353–358. 2002. View Article : Google Scholar : PubMed/NCBI
22	Davis E, Teng H, Bilican B, Parker MI, Liu B, Carriera S, Goding CR and Prince S: Ectopic Tbx2 expression results in polyploidy and cisplatin resistance. Oncogene. 27:976–984. 2008. View Article : Google Scholar : PubMed/NCBI
23	Wansleben S, Davis E, Peres J and Prince S: A novel role for the anti-senescence factor TBX2 in DNA repair and cisplatin resistance. Cell Death Dis. 4:e8462013. View Article : Google Scholar : PubMed/NCBI
24	Ismail A and Bateman A: Expression of TBX2 promotes anchorage-independent growth and survival in the p53-negative SW13 adrenocortical carcinoma. Cancer Lett. 278:230–240. 2009. View Article : Google Scholar : PubMed/NCBI
25	Inoue Y, Fukuda T, Nanno S, Awazu Y, Shimomura M, Matsubara H, Yamauchi M, Yasui T and Sumi T: T-box 2 expression is a useful indicator of the response to neoadjuvant chemotherapy for patients with locally advanced uterine cervical squamous cell carcinoma. Oncol Lett. 22:7552021. View Article : Google Scholar : PubMed/NCBI
26	Tasaka R, Fukuda T, Shimomura M, Inoue Y, Wada T, Kawanishi M, Yasui T and Sumi T: TBX2 expression is associated with platinum-sensitivity of ovarian serous carcinoma. Oncol Lett. 15:3085–3090. 2018.PubMed/NCBI
27	Sinicrope FA, Ruan SB, Cleary KR, Stephens LC, Lee JJ and Levin B: bcl-2 and p53 oncoprotein expression during colorectal tumorigenesis. Cancer Res. 55:237–241. 1995.PubMed/NCBI
28	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
29	de Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B, Tous S, Felix A, Bravo LE, Shin HR, et al: Human papillomavirus genotype attribution in invasive cervical cancer: A retrospective cross-sectional worldwide study. Lancet Oncol. 11:1048–1056. 2010. View Article : Google Scholar : PubMed/NCBI
30	Peres J, Davis E, Mowla S, Bennett DC, Li JA, Wansleben S and Prince S: The highly homologous T-box transcription factors, TBX2 and TBX3, have distinct roles in the oncogenic process. Genes Cancer. 1:272–282. 2010. View Article : Google Scholar : PubMed/NCBI
31	Jacobs JJ, Keblusek P, Robanus-Maandag E, Kristel P, Lingbeek M, Nederlof PM, van Welsem T, van de Vijver MJ, Koh EY, Daley GQ and van Lohuizen M: Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19(ARF)) and is amplified in a subset of human breast cancers. Nat Genet. 26:291–299. 2000. View Article : Google Scholar : PubMed/NCBI
32	Fujiwara K, Daido S, Yamamoto A, Kobayashi R, Yokoyama T, Aoki H, Iwado E, Shinojima N, Kondo Y and Kondo S: Pivotal role of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 in apoptosis and autophagy. J Biol Chem. 283:388–397. 2008. View Article : Google Scholar : PubMed/NCBI
33	Wang H, Zhu LJ, Yang YC, Wang ZX and Wang R: MiR-224 promotes the chemoresistance of human lung adenocarcinoma cells to cisplatin via regulating G1/S transition and apoptosis by targeting p21(WAF1/CIP1). Br J Cancer. 111:339–354. 2014. View Article : Google Scholar : PubMed/NCBI
34	Awazu Y, Fukuda T, Noda T, Uchikura E, Nanno S, Imai K, Yamauchi M, Yasui T and Sumi T: CLPTM1L expression predicts recurrence of patients with intermediate- and high-risk stage IB-IIB cervical cancer undergoing radical hysterectomy followed by TP as adjuvant chemotherapy. Oncol Lett. 26:3532023. View Article : Google Scholar : PubMed/NCBI