Significance of S100P as a biomarker in diagnosis, prognosis and therapy of opisthorchiasis‐associated cholangiocarcinoma

• Published in: International journal of cancer 2016-01, Vol.138 (2), p.396-408
• Main Authors: Wu, Zhiliang, Boonmars, Thidarut, Nagano, Isao, Boonjaraspinyo, Sirintip, Srinontong, Piyarat, Ratasuwan, Panaratana, Narong, Khuntikeo, Nielsen, Phuangphaka Sadee, Maekawa, Yoichi
• Format: Article
• Language: English
• Subjects: Aged; Antineoplastic Agents - therapeutic use; Apoptosis; Bile Duct Neoplasms - diagnosis; Bile Duct Neoplasms - drug therapy; Bile Duct Neoplasms - parasitology; biomarker; Biomarkers, Tumor - analysis; Blotting, Western; Calcium-Binding Proteins - analysis; Calcium-Binding Proteins - biosynthesis; Cancer; Cell cycle; cholangiocarcinoma; Cholangiocarcinoma - diagnosis; Cholangiocarcinoma - drug therapy; Cholangiocarcinoma - parasitology; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunohistochemistry; Male; Medical prognosis; Medical research; Middle Aged; Neoplasm Proteins - analysis; Neoplasm Proteins - biosynthesis; Opisthorchiasis - complications; Prognosis; Real-Time Polymerase Chain Reaction; RNA, Small Interfering; S100P; shRNA; Transfection
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.29721

Cholangiocarcinoma (CCA) is a malignancy of bile duct with the difficulty in early diagnosis, poor prognosis and less alternation in therapy. S100P is a member of S100 family proteins and plays important roles in cancers. We investigated the S100P expression and its correlation with clinicopathology in 78 cases of opisthorchiasis‐associated CCA, and the effects of S100P knockdown with shRNA interference on the proliferation, cell cycle, migration, apoptosis and sensitivity to anti‐cancer drug. Extremely high expression of S100P mRNA was detected in the CCA tumor tissues. The increased S100P protein expression was immunohistochemically confirmed and localized in the CCA cytoplasm and/or nuclei as well as in the hyperneoplasia and dysplasia bile ducts, but not in normal bile ducts. The intensity of immunostaining was correlated with survival, tumor stage and metastasis, and the high expression could be an independent prognostic factor. High levels of S100P were detected in the serum and bile fluid of CCA patients. The shRNA‐mediated knockdown of S100P expression inhibited the proliferation in vitro and in vivo, and migration of CCA cells, arrested cell cycle with the up‐regulated expression of cell cycle arrest related factors, p21, p27, GADD45A, and 14‐3‐3 zeta. S100P knockdown also promoted CCA cell apoptosis by up‐regulating expression of apoptosis related factors, DR5, TRADD, caspase 3 and BAX, and increased the sensitivity of CCA cells to the chemotherapeutic agents sunitinib and apigenin. Taken together, this study indicates that S100P might be a promising biomarker for the diagnosis, prognosis and therapy of CCA. What's new? Infection with the parasite Opisthorchis viverrini is an important risk factor for cholangiocarcinoma (CCA), though methods to detect infection and diagnose and monitor CCA development are limited. In this study, expression of the Ca2+‐binding protein S100P was found to be significantly elevated in opisthorchiasis‐associated CCA tumor tissue, and its expression levels were associated with patient survival. Hence, S100P may be a prognostic marker in CCA. Knockdown of S100P expression inhibited CCA proliferation, induced cell cycle arrest, favored apoptosis, and enhanced CCA cell sensitivity to the drugs sunitinib and apigenin.