Activating mutations in PTPN3 promote cholangiocarcinoma cell proliferation and migration and are associated with tumor recurrence in patients

Qiang Gao, Ying Jun Zhao, Xiao Ying Wang, Wei Jie Guo, Song Gao, Lin Wei, Jie Yi Shi, Guo Ming Shi, Zhi Chao Wang, Yuan Nv Zhang, Ying Hong Shi, Jie Ding, Zhen Bin Ding, Ai Wu Ke, Zhi Dai, Fei Zhen Wu, Hui Wang, Zhao Ping Qiu, Zhi Ao Chen, Zhen Feng ZhangShuang Jian Qiu, Jian Zhou, Xiang Huo He, Jia Fan

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

Background & Aims The pathogenesis of intrahepatic cholangiocarcinoma (ICC), the second most common hepatic cancer, is poorly understood, and the incidence of ICC is increasing worldwide. We searched for mutations in human ICC tumor samples and investigated how they affect ICC cell function. Methods We performed whole exome sequencing of 7 pairs of ICC tumors and their surrounding nontumor tissues to detect somatic alterations. We then screened 124 pairs of ICC and nontumor samples for these mutations, including 7 exomes. We compared mutations in PTPN3 with tumor recurrence in 124 patients and PTPN3 expression levels with recurrence in 322 patients (the combination of both in 86 patients). The functional effects of PTPN3 variations were determined by RNA interference and transgenic expression in cholangiocarcinoma cell lines (RBE, HCCC-9810, and Huh28). Results Based on exome sequencing, pathways that regulate protein phosphorylation were among the most frequently altered in ICC samples and genes encoding protein tyrosine phosphatases (PTPs) were among the most frequently mutated. We identified mutations in 9 genes encoding PTPs in 4 of 7 ICC exomes. In the prevalence screen of 124 paired samples, 51.6% of ICCs contained somatic mutations in at least 1 of 9 PTP genes; 41.1% had mutations in PTPN3. Transgenic expression of PTPN3 in cell lines increased cell proliferation, colony formation, and migration. PTPN3L232R and PTPN3L384H, which were frequently detected in ICC samples, were found to be gain-of-function mutations; their expression in cell lines further increased cell proliferation, colony formation, and migration. ICC-associated variants of PTPN3 altered phosphatase activity. Patients whose tumors contained activating mutations or higher levels of PTPN3 protein than nontumor tissues had higher rates of disease recurrence than patients whose tumors did not have these characteristics. Conclusions Using whole exome sequencing of ICC samples from patients, we found that more than 40% contain somatic mutations in PTPN3. Activating mutations in and high expression levels of PTPN3 were associated with tumor recurrence.

Original languageEnglish (US)
Pages (from-to)1397-1407
Number of pages11
JournalGastroenterology
Volume146
Issue number5
DOIs
StatePublished - May 2014
Externally publishedYes

Keywords

  • Carcinogenesis
  • Keywords
  • Liver Cancer
  • Phosphorylation
  • Signal Transduction

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Gao, Q., Zhao, Y. J., Wang, X. Y., Guo, W. J., Gao, S., Wei, L., Shi, J. Y., Shi, G. M., Wang, Z. C., Zhang, Y. N., Shi, Y. H., Ding, J., Ding, Z. B., Ke, A. W., Dai, Z., Wu, F. Z., Wang, H., Qiu, Z. P., Chen, Z. A., ... Fan, J. (2014). Activating mutations in PTPN3 promote cholangiocarcinoma cell proliferation and migration and are associated with tumor recurrence in patients. Gastroenterology, 146(5), 1397-1407. https://doi.org/10.1053/j.gastro.2014.01.062