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Molecular variation of different geographic populations and cholangiocarcinoma (CCA) subtypes indicate CCA’s potential genomic heterogeneity and novel genomic features. We analyzed exome-sequencing data of 87 perihialr cholangiocarcinoma (pCCA) and 261 intrahepatic cholangiocarcinoma (iCCA) from 3 Asian centers (including 43 pCCAs and 24 iCCAs from our center). Patients with iCCA presented higher tumor mutation burden and copy number alteration burden (CNAB) than pCCA patients, and CNAB indicated a poorer pCCA prognosis. In our newly identified 12 significantly mutated genes and 5 focal CNA regions, post-transcriptional modification-related novel driver genes METTL14 and RBM10 are prone to occur in pCCA. We demonstrated the tumor-suppressing functional role of METTL14, a major RNA N6-adenosine methyltransferase (m6A), and its loss-of-function mutation R298H may function through m6A modification on new driver gene MACF1. Our results may be valuable for better understanding of post-transcriptional modification effects CCA development, and similarities and differences between pCCA and iCCA.

Molecular variation between geographical populations and subtypes indicate potential genomic heterogeneity and novel genomic features within CCA. Here, we analyze exome-sequencing data of 87 perihilar cholangiocarcinoma (pCCA) and 261 intrahepatic cholangiocarcinoma (iCCA) cases from 3 Asian centers (including 43 pCCAs and 24 iCCAs from our center). iCCA tumours demonstrate a higher tumor mutation burden and copy number alteration burden (CNAB) than pCCA tumours, and high CNAB indicates a poorer pCCA prognosis. We identify 12 significantly mutated genes and 5 focal CNA regions, and demonstrate common mutations in post-transcriptional modification-related potential driver genes METTL14 and RBM10 in pCCA tumours. Finally we demonstrate the tumour-suppressive role of METTL14, a major RNA N6-adenosine methyltransferase (m6A), and illustrate that its loss-of-function mutation R298H may act through m6A modification on potential driver gene MACF1. Our results may be valuable for better understanding of how post-transcriptional modification can affect CCA development, and highlight both similarities and differences between pCCA and iCCA.

Background/Aims: Aberrant expression of Tip60 is associated with progression in many cancers. However, the role of Tip60 in cancer progression remains contradictory. The aim of this study was to investigate the clinical significance, biological functions and underlying mechanisms of Tip60 deregulation in cholangiocarcinoma (CCA) for the first time. Methods: Quantitative real-time PCR (QRT-PCR), western blotting and immunohistochemistry staining (IHC) were carried out to measure Tip60 expression in CCA tissues and cell lines. Kaplan–Meier analysis and the log-rank test were used for survival analysis. In vitro, cell proliferation was evaluated by flow cytometry and CCK-8, colony formation, and EDU assays. Migration/ invasion was evaluated by trans-well assays. Phosphokinase array was used to confirm the dominant signal regulated by Tip60. Tumor growth and metastasis were demonstrated in vivo using a mouse model. Results: Tip60 was notably downregulated in CCA tissues, which was associated with greater tumor size, venous invasion, and TNM stage. Down-regulation of Tip60 was associated with tumor progression and poorer survival in CCA patients. In vitro and in vivo studies demonstrated that Tip60 suppressed growth and metastasis throughout the progression of CCA. We further identified the PI3K/AKT pathway as a dominant signal of Tip60 and suggested that Tip60 regulated CCA cell proliferation and metastasis via PT3K-AKT pathway. Pearson analysis revealed that PTEN was positively correlated with the Tip60 level in CCA tissues. Conclusion: Tip60, as a tumor suppressor in CCA via the PI3K/AKT pathway, might be a promising therapeutic target or prognostic marker for CCA.

// Sheng Han 1, * , Dong Wang 1, * , Guohua Tang 1, * , Xinxiang Yang 1 , Chenyu Jiao 1 , Renjie Yang 1 , Yaodong Zhang 1 , Liqun Huo 1 , Zicheng Shao 1 , Zefa Lu 1 , Jiawei Zhang 1 and Xiangcheng Li 1 1 Liver Transplantation Center of The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China * These authors contributed equally to this work Correspondence to: Xiangcheng Li, email: drxcli@njmu.edu.cn Keywords: CCA, miRNA, proliferation, metastasis, prognosis Received: January 16, 2017 Accepted: April 19, 2017 Published: May 12, 2017 ABSTRACT Background & Aims: Aberrant expression of microRNAs is associated with many cancers progression. Many studies have shown that miR-16 is down-regulated in many cancers. However, its role in cholangiocarcinoma (CCA) is unknown. Methods: Quantitative real-time PCR (qRT-PCR) was developed to measure miR-16 expression in CCA tissues and cell lines. CCK-8, colony formation and transwell assays were used to reveal the role of miR-16 in CCA cell proliferation and malignant transformation in vitro . The loss-and-gain function was further validated by subcutaneous xenotransplantation and tail vein injection xenotransplantation model in vivo . Dual-luciferase reporter assay was performed to validate the relationship of miR-16 with YAP1. Results: MiR-16 was notably downregulated in CCA tissues, which was associated with tumor size, metastasis, and TNM stage. Both in vitro and in vivo studies demonstrated that miR-16 could suppress proliferation, invasion and metastasis throughout the progression of CCA. We further identified YAP1 as a direct target gene of miR-16 and found that miR-16 could regulate CCA cell growth and invasion in a YAP1-dependent manner. In addition, YAP1 was markedly upregulated in CCA tissues, which was reversely correlated with miR-16 level in tissue samples. Besides, Down-regulation of miR-16 was remarkably associated with tumor progression and poor survival in CCA patients through a Kaplan–Meier survival analysis. Conclusions: miR-16, as a novel tumor suppressor in CCA through directly targeting YAP1, might be a promising therapeutic target or prognosis biomarker for CCA.