Targeting WISP1 to sensitize esophageal squamous cell carcinoma to irradiation.
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.
Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China.
Hongfang
H
Zhang
Department of Radiotherapy, Huai'an First People's Hospital, Huai'an, China.
Honglei
H
Luo
Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China.
Zhaoyang
Z
Hu
Department of Radiotherapy, Huai'an First People's Hospital, Huai'an, China.
Jin
J
Peng
Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China.
Zhenzhen
Z
Jiang
Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China.
Tao
T
Song
Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China.
Bo
B
Wu
Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China.
Jing
J
Yue
Department of Pathology, Hangzhou Cancer Hospital, Hangzhou, China.
Rongjing
R
Zhou
Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China.|Department of Bio-Informatics, Hangzhou Cancer Hospital, Hangzhou, China.
Ruifei
R
Xie
Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China.
Tian
T
Chen
Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China.
Shixiu
S
Wu
D000818:Animals; D055511:CCN Intercellular Signaling Proteins / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D004249:DNA Damage; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D064593:Heterografts; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D011836:Radiation Tolerance; D014162:Transfection; D060449:Wnt Signaling Pathway
D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases
ESCC; WISP1; mechanisms; prognostic significance; radioresistance