Biology subjects

Chayama, K.

Publications and source records attributed to Chayama, K..

2 recordsLinked to original sources

bioRxiv2018

HBx enhances CPAP expression via interacting with CREB to promote hepatocarcinogenesis in HBV-associated HCC

Hepatitis B virus (HBV) encoded non-structure protein X (HBx) can promote cell proliferation, migration, and anti-apoptosis via activating several transcription factors and increasing their downstream gene expression in HBV-infected liver cells. Our previous report suggested that centrosomal P4.1-associated protein (CPAP) is required for HBx-mediated NF-{kappa}B activation. Here, we found that, upon HBV infection, overexpressed HBx can transcriptionally up-regulate CPAP via interacting with CREB. CPAP can directly interact with HBx to promote HBx-mediated cell proliferation and migration; and SUMO modification of CPAP is involved in interacting with HBx. Interestingly, CPAP can increase the HBx protein stability in an NF-{kappa}B-dependent manner; and overexpressed CPAP and HBx is positively correlated with the activation status of NF-{kappa}B in HCC. Increased expression of CREB and CPAP mRNAs exists in the high-risk group with a lower survival rate in hepatocellular carcinoma (HCC). These results suggest that the reciprocal regulation between CPAP and HBx may provide a microenvironment to facilitate HCC development via enhancing NF-{kappa}B activation, inflammatory cytokine production, and cancer maligancies. The findings of this study not only shed light on the role of CPAP in HBV-associated HCC, but also provide CPAP as a potential target for HBV-related HCC therapy.\n\nAuthor SummaryIn this study, we address a novel molecular mechanism for the collaboration between overexpressed HBx and CPAP in promoting hepatocarcinogenesis in HBV-associated HCC. Upon HBV infection, HBx is overexpressed and interacts with CREB to transcriptionally activate CPAP; the HBx/CPAP interaction promotes hepatocarcinogenesis. Clinical analysis found that co-overexpressed CPAP and CREB exist in the high-risk group with a lower survival rate in HCC. Additionally, overexpressed CPAP contributes to HBx protein stability in a NF-{kappa}B-dependent pathway. Our study provides a potential translational application in targeting CREB-CPAP axis in HBV-associated HCC.

cancer biology↗

bioRxiv2017

In-depth characterization of the cisplatin mutational signature in a human cell line and in esophageal and liver tumors

Background and aimsCisplatin reacts with DNA, and thereby likely generates a characteristic pattern of somatic mutations, called a mutational signature. Despite widespread use of cisplatin in cancer treatment and its role in contributing to secondary malignancies, its mutational signature has not been delineated. We hypothesize that cisplatins mutational signature can serve as a biomarker to identify cisplatin mutagenesis in suspected secondary malignancies. Knowledge of which tissues are at risk of developing cisplatin-induced secondary malignancies could lead to guidelines for non-invasive monitoring for secondary malignancies after cisplatin chemotherapy.\n\nMethodsWe performed whole genome sequencing of 10 independent clones of cisplatin-exposed MCF-10A and HepG2 cells, and delineated the patterns of single- and dinucleotide mutations in terms of flanking sequence, transcription strand bias, and other characteristics. We used the mSigAct signature presence test and non-negative matrix factorization to search for cisplatin mutagenesis in hepatocellular carcinomas and esophageal adenocarcinomas.\n\nResultsAll clones showed highly consistent patterns of single- and dinucleotide substitutions. The proportion of dinucleotide substitutions was high: 8.1% of single nucleotide substitutions were part of dinucleotide substitutions, presumably due to cisplatins propensity to form intra-and inter-strand crosslinks between purine bases in DNA. We identified likely cisplatin exposure in 9 hepatocellular carcinomas and 3 esophageal adenocarcinomas. All hepatocellular carcinomas for which clinical data were available and all esophageal cancers indeed had histories of cisplatin treatment.\n\nConclusionsWe experimentally delineated the single- and dinucleotide mutational signature of cisplatin. This signature enabled us to detect previous cisplatin exposure in human hepatocellular carcinomas and esophageal adenocarcinomas with high confidence.

cancer biology↗