Low expression of ARID1A is associated with poor prognosis in patients with IHCC, and thus may be a potential prognostic biomarker candidate in IHCC.

Downregulation of KIF1B in HCC tissues is associated with poor prognosis; additional clinical studies are needed to confirm whether KIF1B can serve as a prognostic marker.

PU box binding protein (PU.1) is a critical transcription factor involved in many pathological processes. However, its exact role in activation of hepatic stellate cells (HSCs) and liver fibrosis was rarely reported. Here, we found that, in HSCs of PU.1+/− mice, Sirt1 mRNA expression was not changed but Sirt1 protein was significantly increased, suggesting its promoting role in Sirt1 translation. We then isolated HSCs from wild-type (WT) and PU.1+/− mice, and the pcDNA-PU.1 expression vector was transfected into PU.1+/− HSCs. We checked the levels of miR-34a and miR-29c, two Sirt1-targetting miRNAs, and protein levels of PU.1 and Sirt1. The results showed that miR-34a/-29c were significantly reduced and Sirt1 protein was increased in PU.1+/− HSCs, compared with WT HSCs. Besides, PU.1 overexpression inversed the reduction in miR-34a/-29c levels and the increase in Sirt1 protein in both PU.1+/- HSCs and WT HSCs. Additionally, ChIP-quantitive real-time PCR (qPCR) assay comfirmed that PU.1 was directly bound to both the promoter regions of miR-34a and miR-29c. Importantly, PU.1 overexpression promoted the proliferation, migration, activation, oxidative stress and inflammatory response in WT HSCs, while the promotion could be inversed by either overexpression of Sirt1 or inhibition of miR-34a/-29c. Moreover, animal model of liver fibrosis was established by intraperitoneal injections of thioacetamide (TAA) in WT and PU.1+/− mice, respectively. Compared with the WT mice, PU.1+/− mice displayed a lower fibrotic score, less collagen content, better liver function, and lower levels of oxidative stress and inflammatory response. In conclusion, PU.1 suppresses Sirt1 translation via transcriptional promotion of miR-34a/-29c, thus promoting Sirt1-mediated HSC activation and TAA-induced hepatic fibrosis.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies in China and has limited therapeutic options. Genomic alterations in HCC had been widely explored and some prognostic genomic alterations were identified. Different etiologic characteristics were discovered in Chinese HCC patients compared with Western population; however, the genomic profiles of Chinese patients had not been thoroughly elucidated. Methods: FFPE tumor samples of 94 Chinese HCC patients, including 79 males and 15 females with a median age of 56, were collected for next-generation sequencing (NGS)-based 450 genes panel assay. Genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, and gene rearrangement and fusions were assessed. Gene Ontology (GO) analysis was conducted with the genes whose variation rates were higher than 5% (N = 22). The TCGA HCC dataset with 198 patients was used to assess the prognostic value of the significantly enriched GO terms. Results: The top 10 highly mutant genes in the 94 Chinese HCC cohort were TP53 (64.9%), TERT (31.9%), CTNNB1 (23.4%), AXIN1 (16.0%), STK24 (12.8%), RB1 (11.7%), CCND1 (9.6%), ARID1A (9.6%), LRPIB (8.5%) and ARID2 (8.5%). The Gene Ontology analysis revealed these gene alterations were significantly associated with pivotal signal pathways and cell proliferation including phosphatidylinositol phosphorylation, protein kinase B signaling, cell cycle arrest, and G1/S transition of mitotic cell cycle. The G1/S transition-related genes included TP53, TERT, RB1, CCND1 and CDKN2A. Moreover, the TCGA HCC patients with mutations of G1/S phase transition and mitotic cell cycle-related genes had a poor survival (p = 0.029). Conclusions: Our study showed that Chinese HCC patients had different genomic alteration profile compared with Western population. The most frequent mutant gene in Chinese HCC was TP53 in 65% of the HCC patients, compared to 31% in the TCGA dataset (PMID:28622513). Genomic alterations in G1/S transition of mitotic cell cycle-related genes in Chinese HCC patients might be a negative prognostic factor. Our preliminary result suggested that functional analysis of HCC genomic alteration profile could have prognostic utility. Citation Format: Bingyuan Zhang, Tianqiang Song, Pingzhou Yang, Songzhu Yang, Chao Guo, Lei Li, Shuang Ren, Maolin Yan, Weiyu Hu, Honglin Guo, Yongjian Zhang, Yanlin Li, Weifeng Wang, Kai Wang, Ming Yao. G1/S transition-related gene mutations associated with survival of hepatocellular carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4607.