STAT3 enhances radiation-induced tumor migration, invasion and stem-like properties of bladder cancer

Wang,Fang; Ma,Xiangli; Mao,Guangmin; Zhang,Xiangyan; Kong,Zhaolu

doi:10.3892/mmr.2020.11728

STAT3 enhances radiation-induced tumor migration, invasion and stem-like properties of bladder cancer

Authors:
- Fang Wang
- Xiangli Ma
- Guangmin Mao
- Xiangyan Zhang
- Zhaolu Kong
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Affiliations: Department of Radiobiology, Institute of Radiation Medicine, Fudan University, Shanghai 200032, P.R. China
Published online on: November 24, 2020 https://doi.org/10.3892/mmr.2020.11728
Article Number: 87
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Bladder cancer (BCa) is the most common cancer of the human urinary system, and is associated with poor patient prognosis and a high recurrence rate. Cancer stem cells (CSCs) are the primary cause of tumor recurrence and metastasis, possessing self‑renewal properties and resistance to radiation therapy. Our previous studies indicated that phosphorylated signal transduction and transcription activator 3 (STAT3) may be a potential biomarker to predict radiation tolerance and tumor recurrence in patients with BCa, following conventional radiotherapy. The aim of the present study was to investigate the underlying mechanism of STAT3 in the radio‑resistance of BCa cells. It was found that fractionated irradiation promoted the activation of two STAT3‑associated CSCs signaling pathways in BCa cells, namely suppressor of variegation 3‑9 homolog 1/GATA binding protein 3/STAT3 and Janus kinase 2/STAT3. Surviving cells exhibited elevated migratory and invasive abilities, enhanced CSC‑like characteristics and radio‑resistance. Furthermore, knockdown of STAT3 expression or inhibition of STAT3 activation markedly decreased the self‑renewal ability and tumorigenicity of radiation‑resistant BCa cells. Kaplan‑Meier analysis revealed that decreased STAT3 mRNA levels were associated with increased overall survival times in patients with BCa. Taken together, these data indicated that STAT3 may be an effective therapeutic target for inhibiting the progression, metastasis and recurrence of BCa in patients receiving radiotherapy.

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1	Kaufman DS, Shipley WU and Feldman ASJL: Bladder Cancer. Lancet. 374:239–249. 2009. View Article : Google Scholar
2	Dong F, Xu T, Shen Y, Zhong S, Chen S, Ding Q and Shen Z: Dysregulation of miRNAs in bladder cancer: Altered expression with aberrant biogenesis procedure. Oncotarget. 8:27547–27568. 2017. View Article : Google Scholar
3	Park JC, Citrin DE, Agarwal PK and Apolo AB: Multimodal management of muscle-invasive bladder cancer. Curr Probl Cancer. 38:80–108. 2014. View Article : Google Scholar
4	Madersbacher S, Hochreiter W, Burkhard F, Thalmann GN, Danuser H, Markwalder R and Studer UE: Radical cystectomy for bladder cancer today - a homogeneous series without neoadjuvant therapy. J Clin Oncol. 21:690–696. 2003. View Article : Google Scholar
5	Smith AB, Jaeger B, Pinheiro LC, Edwards LJ, Tan HJ, Nielsen ME and Reeve BB: Impact of bladder cancer on health-related quality of life. BJU Int. 121:549–557. 2018. View Article : Google Scholar
6	Bajaj A, Martin B, Bhasin R, Hentz C, Block AM, Harkenrider MM and Solanki AA: The impact of academic facility type and case volume on survival in patients undergoing curative radiation therapy for muscle-invasive bladder cancer. Int J Radiat Oncol Biol Phys. 100:851–857. 2018. View Article : Google Scholar
7	Mitin T, Dengina N, Chernykh M, Usychkin S, Gladkov O, Degnin C, Chen Y, Nosov D, Tsimafeyeu I, Thomas CR Jr, et al: Management of muscle invasive bladder cancer with bladder preservation in Russia: A survey-based analysis of current practice and the impact of an educational workshop on clinical expertise. J Cancer Educ. Mar 4–2020.(Epub ahead of print). doi: 10.1007/s13187-020-01728-y. View Article : Google Scholar
8	Shimura T: Acquired radioresistance of cancer and the AKT/GSK3β/cyclin D1 overexpression cycle. J Radiat Res (Tokyo). 52:539–544. 2011. View Article : Google Scholar
9	Sharda A, Rashid M, Shah SG, Sharma AK, Singh SR, Gera P, Chilkapati MK and Gupta S: Elevated HDAC activity and altered histone phospho-acetylation confer acquired radio-resistant phenotype to breast cancer cells. Clin Epigenetics. 12:42020. View Article : Google Scholar
10	Anuja K, Kar M, Chowdhury AR, Shankar G, Padhi S, Roy S, Akhter Y, Rath AK and Banerjee B: Role of telomeric RAP1 in radiation sensitivity modulation and its interaction with CSC marker KLF4 in colorectal cancer. Int J Radiat Biol. 96:790–802. 2020. View Article : Google Scholar
11	Pajonk F, Vlashi E and McBride WH: Radiation resistance of cancer stem cells: The 4 R's of radiobiology revisited. Stem Cells. 28:639–648. 2010. View Article : Google Scholar
12	Vlashi E and Pajonk F: Cancer stem cells, cancer cell plasticity and radiation therapy. Semin Cancer Biol. 31:28–35. 2015. View Article : Google Scholar
13	Bighetti-Trevisan RL, Sousa LO, Castilho RM and Almeida LO: Cancer stem cells: Powerful targets to improve current anticancer therapeutics. Stem Cells Int. 2019:96180652019. View Article : Google Scholar
14	Ishiguro T, Ohata H, Sato A, Yamawaki K, Enomoto T and Okamoto K: Tumor-derived spheroids: Relevance to cancer stem cells and clinical applications. Cancer Sci. 108:283–289. 2017. View Article : Google Scholar
15	Galoczova M, Coates P and Vojtesek B: STAT3, stem cells, cancer stem cells and p63. Cell Mol Biol Lett. 23:122018. View Article : Google Scholar
16	Pattabiraman DR and Weinberg RA: Tackling the cancer stem cells - what challenges do they pose? Nat Rev Drug Discov. 13:497–512. 2014. View Article : Google Scholar
17	Lin L, Fuchs J, Li C, Olson V, Bekaii-Saab T and Lin J: STAT3 signaling pathway is necessary for cell survival and tumorsphere forming capacity in ALDH⁺/CD133⁺ stem cell-like human colon cancer cells. Biochem Biophys Res Commun. 416:246–251. 2011. View Article : Google Scholar
18	Mao G, Yao Y and Kong Z: Long term exposure to γ rays induces radioresistance and enhances the migration ability of bladder cancer cells. Mol Med Rep. 18:5834–5840. 2018.
19	Chang R, He H, Mao G and Kong Z: Upregulating DAB2IP expression via EGR-1 inhibition, a new approach for overcoming fractionated-irradiation-induced cross-tolerance to ionizing radiation and mitomycin C in tumor cells. Int J Radiat Biol. 93:386–393. 2017. View Article : Google Scholar
20	Sen N, Che X, Rajamani J, Zerboni L, Sung P, Ptacek J and Arvin AM: Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis. Proc Natl Acad Sci USA. 109:600–605. 2012. View Article : Google Scholar
21	Yang Z, He L, Lin K, Zhang Y, Deng A, Yong Liang Y, Li C and Wen T: The KMT1A-GATA3-STAT3 circuit is a novel self-renewal signaling of human bladder cancer stem cells. Clin Cancer Res. 23:6673–6685. 2017. View Article : Google Scholar
22	Nagy Á, Lánczky A, Menyhárt O and Győrffy B: Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets. Sci Rep. 8:92272018. View Article : Google Scholar
23	Livak and Schmittgen, . Analysis of relative gene expression data using real-time quantitative PCR and the 2-DDct method. Methods. 25:402–408. 2001. View Article : Google Scholar
24	Eun K, Ham SW and Kim H: Cancer stem cell heterogeneity: origin and new perspectives on CSC targeting. BMB Rep. 50:117–125. 2017. View Article : Google Scholar
25	Ahmad G and Amiji MM: Cancer stem cell-targeted therapeutics and delivery strategies. Expert Opin Drug Deliv. 14:997–1008. 2017. View Article : Google Scholar
26	Tran MN, Goodwin Jinesh G, McConkey DJ and Kamat AM: Bladder cancer stem cells. Curr Stem Cell Res Ther. 5:387–395. 2010. View Article : Google Scholar
27	Abubaker K, Luwor RB, Zhu H, McNally O, Quinn MA, Burns CJ, Thompson EW, Findlay JK and Ahmed N: Inhibition of the JAK2/STAT3 pathway in ovarian cancer results in the loss of cancer stem cell-like characteristics and a reduced tumor burden. BMC Cancer. 14:3172014. View Article : Google Scholar
28	Gao L, Li FS, Chen XH, Liu QW, Feng J B, Liu QJ and Su X: Radiation induces phosphorylation of STAT3 in a dose- and time-dependent manner. Asian Pac J Cancer Prev. 15:6161–6164, 201. View Article : Google Scholar
29	Berdik C: Unlocking bladder cancer. Nature. 551:S34–S35. 2017. View Article : Google Scholar
30	Li JY, Li YY, Jin W, Yang Q, Shao ZM and Tian XS: ABT-737 reverses the acquired radioresistance of breast cancer cells by targeting Bcl-2 and Bcl-xL. J Exp Clin Cancer Res. 31:1022012. View Article : Google Scholar
31	Najafi M, Farhood B, Mortezaee K, Kharazinejad E, Majidpoor J and Ahadi R: Hypoxia in solid tumors: A key promoter of cancer stem cell (CSC) resistance. J Cancer Res Clin Oncol. 146:19–31. 2020. View Article : Google Scholar
32	Ohishi T, Koga F and Migita T: Bladder cancer stem-like cells: Their origin and therapeutic perspectives. Int J Mol Sci. 17:172015. View Article : Google Scholar
33	Masliantsev K, Pinel B, Balbous A, Guichet PO, Tachon G, Milin S, Godet J, Duchesne M, Berger A, Petropoulos C, et al: Impact of STAT3 phosphorylation in glioblastoma stem cells radiosensitization and patient outcome. Oncotarget. 9:3968–3979. 2017. View Article : Google Scholar
34	Park SY, Lee CJ, Choi JH, Kim JH, Kim JW, Kim JY and Nam JS: The JAK2/STAT3/CCND2 Axis promotes colorectal cancer stem cell persistence and radioresistance. J Exp Clin Cancer Res. 38:3992019. View Article : Google Scholar
35	Huang S: Regulation of metastases by signal transducer and activator of transcription 3 signaling pathway: clinical implications. Clin Cancer Res. 13:1362–1366. 2007. View Article : Google Scholar