Targeting WISP1 to sensitize esophageal squamous cell carcinoma to irradiation
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Hongfang Zhang1,* Honglei Luo2,*, Zhaoyang Hu1,*, Jin Peng2, Zhenzhen Jiang1, Tao Song1, Bo Wu1, Jing Yue1, Rongjing Zhou3, Ruifei Xie1,4, Tian Chen1 and Shixiu Wu1
1 Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China
2 Department of Radiotherapy, Huai’an First People’s Hospital, Huai’an, China
3 Department of Pathology, Hangzhou Cancer Hospital, Hangzhou, China
4 Department of Bio-Informatics, Hangzhou Cancer Hospital, Hangzhou, China
* These authors contributed equally to this work
Shixiu Wu, email:
Keywords: ESCC, radioresistance, WISP1, prognostic significance, mechanisms
Received: October 21, 2014 Accepted: January 13, 2015 Published: January 31, 2015
Radiotherapy is a primary treatment modality for esophageal squamous cell carcinoma (ESCC). However, most of patients benefited little from radiotherapy due to refractory radioresistance. We found that WISP1, a downstream target gene of Wnt/β-catenin pathway, was re-expressed in 67.3 % of ESCC patients as an oncofetal gene. Expression of WISP1 predicted prognosis of ESCC patients treated with radiotherapy. Overall survival in WISP1-positive patients was significantly poorer than in WISP1-negative patients. Serum concentration of WISP1 after radiotherapy reversely correlated with relapse-free survival. Gain and loss of function studies confirmed that WISP1 mediated radioresistance both in esophageal squamous cancer cells and in xenograft tumor models. Further studies revealed that WISP1 contributed to radioresistance primarily by repressing irradiation-induced DNA damage and activating PI3K kinase. LncRNA BOKAS was up-regulated following radiation and promoted WISP1 expression and resultant radioresistance. Furthermore, WISP1 facilitated its own expression in response to radiation, creating a positive feedback loop and increased radioresistance. Our study revealed WISP1 as a potential target to overcome radioresistance in ESCC.
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