CK19-positive Hepatocellular Carcinoma is a Characteristic Subtype.

The heterogeneity of hepatocellular carcinoma (HCC) commonly leads to therapeutic failure of HCC. Cytokeratin 19 (CK19) is well acknowledged as a biliary/progenitor cell marker and a marker of tumor stem cell. CK19-positive HCCs demonstrate aggressive behaviors and poor outcomes which including worse overall survival and early tumor recurrence after hepatectomy and liver transplantation. CK19-positive HCCs are resistant to chemotherapies as well as local treatment. This subset of HCC is thought to derive from liver progenitor cells and can be induced by extracellular stimulation such as hypoxia. Besides being a stemness marker, CK19 plays an important role in promoting malignant property of HCC. The regulatory network associated with CK19 expression has been summarized that extracellular stimulations which transmit into cytoplasm through signal transduction pathways (TGF-ß, MAKP/JNK and MEK-ERK1/2), further induce important nuclear transcriptional factors (SALL4, AP1, SP1) to activate CK19 promoter. Novel noncoding RNAs are also involved in the regulation of CK19 expression. TGFßR1 becomes a therapeutic target for CK19-positive HCC. In conclusion, CK19 can be a potential biomarker for predicting poor prognosis after surgical and adjuvant therapies. CK19-pisitive HCCs exhibit distinctive molecular profiling, should be diagnosed and treated as a separate subtype of HCCs.

Endoplasmic reticulum stress triggers delanzomib-induced apoptosis in HCC cells through the PERK/eIF2α/ATF4/CHOP pathway.

For limited clinical benefits and acquired resistance by sorafenib, new therapeutic strategies and molecular targets for the treatment of advanced hepatocellular carcinoma (HCC) are urgently needed. This study aimed to evaluate the potential antitumor effects of the second-generation proteasome inhibitor delanzomib on HCC. The results demonstrated that delanzomib displayed excellent antitumor activity on HCC cells with sensitivity or resistance to sorafenib in a time- and dose-response manner, by inducing G2/M cell cycle arrest and apoptosis in vitro. Cell cycle arrest was associated with the activation of p21/Cdc2/cyclin B1 pathway, and cell apoptosis was confirmed by PARP and caspase-3 cleavage. In addition, delanzomib induced endoplasmic reticulum stress (ERS) in HCC cells by activating the PERK and ERS-associated proteins including p-eIF2α, ATF4 and CHOP. Selective inhibition of eIF2α dephosphorylation by salubrinal could significantly reduce delanzomib-induced apoptosis in HCC cells. In vivo, delanzomib could also exhibit effective antitumor properties on patient-derived xenograft mouse model of HCC with relative low drug-associated cytotoxicity. Compared to control group, 3 and 10 mg/kg of delanzomib significantly reduced the tumor volume by 33.1% and 87.2% respectively after 3 weeks treatment, with no significant change on the body weight and the level of serum biochemical indexes including ALT, AST and BUN. In conclusion, delanzomib could exhibit good pre-clinical antitumor effects against HCC cells by inducing ERS and activating the PERK/eIF2α/ATF4/CHOP pathway, as potential drug candidate on treatment of advanced HCC patients.

CC motif chemokine ligand 16 inhibits the progression of liver cirrhosis via inactivating hepatic stellate cells.

BACKGROUND: Liver cirrhosis results from many forms of chronic damage, characterized by accumulation of extracellular matrix. The present study aimed to explore a potential non-invasive biomarker and its mechanism in the progression of liver cirrhosis. METHODS: Gene Expression Omnibus (GEO) dataset (GSE15654, n = 216) was analyzed to screen genes associated with progression of liver cirrhosis. A total of 181 plasma samples, including healthy control (HC, n = 20), chronic hepatitis B (CHB, n = 77) and HBV-related liver cirrhosis (LC, n = 84), were enrolled for validation. In vitro and in vivo experiments were employed for the mechanistic investigation. RESULTS: GEO dataset analysis showed that relatively low mRNA-expression of CC motif chemokine ligand 16 (CCL16) was associated with elevated Child-Pugh score (P = 0.034) and worse prognosis (P = 0.025). Plasma CCL16 level decreased in a stepwise pattern, with a median concentration of 10.29, 6.57 and 4.47 ng/mL in the HC, CHB and LC groups, respectively (P<0.001). Low plasma CCL16 was significantly related to hepatic dysfunction both in the CHB and LC groups (P<0.05). Combination of CCL16 and ALT showed improved distinguishing capability for LC compared to either alone. In vitro, CCL16 expression was downregulated by lipopolysaccharide and hypoxia. Overexpression of CCL16 from human normal liver cell line (LO2) reduced the extracellular matrix associated proteins (Col1 and Col4) in human hepatic stellate cell line (LX-2). In vivo, the pathological feature of cirrhosis was alleviated by the hepatocyte-specific expression of CCL16. CONCLUSIONS: CCL16 could be a feasible plasma marker to predict the occurrence and progression of liver cirrhosis. CCL16 might impact liver cirrhosis through inactivating hepatic stellate cells.

17-beta-hydroxysteroid dehydrogenase 13 inhibits the progression and recurrence of hepatocellular carcinoma.

BACKGROUND: Our previous study showed that 17-beta-hydroxysteroid dehydrogenase 13 (HSD17B13) is down-regulated in hepatocellular carcinoma (HCC). But its function in HCC remains unknown. This study aimed to reveal the function of HSD17B13 and its clinical significance in HCC. METHODS: mRNA levels of HSD17B13 were analyzed in cohort 1 (30 normal, 30 HBV cirrhosis, 60 HBV-related HCC and 60 peritumoral tissue) by real-time PCR. HSD17B13 protein was evaluated in cohort 2 (15 normal, 33 HBV-cirrhosis, 12 dysplastic nodules, 34 HBV-related HCC, and 9 metastatic HCC) using immunohistochemistry. The association between HSD17B13 and the survival of HCC patients was analyzed in cohort 3 (n = 88). The inhibitory mechanism of HSD17B13 on HCC was explored . RESULTS: The mRNA of HSD17B13 and its protein expression were significantly down-regulated in HCC compared to non-tumor specimens (P < 0.001). The sensitivity, specificity and area under curve (AUC) values of HSD17B13 expression levels for HCC detection were 81.7%, 83.7% and 0.856, respectively (P < 0.001). Lower HSD17B13 in peritumoral tissue was an independent risk factor of worse recurrence free survival of HCC patients (HR: 0.41; 95% CI: 0.20-0.83; P = 0.014). The study in Huh 7 and SK-HEP-1 cells showed that HSD17B13 induced an accumulation of cells in G1 phase and reduction of cells in S and G2 phases via up-regulating the expression of P21, P27 and MMP2. CONCLUSIONS: Lower HSD17B13 in peritumoral tissues was associated with worse recurrence free survival and overall survival of HCC patients. HSD17B13 delayed G1/S progression of HCC cells. HSD17B13 may be a therapeutic target for the treatment of HCC.