Down‐regulation of the cyclin‐dependent kinase inhibitor p57 is mediated by Jab1/Csn5 in hepatocarcinogenesis

Abstract

Down-regulation of p57 (KIP2) cyclin-dependent kinase inhibitors accelerates the growth and invasion of hepatocellular carcinoma (HCC), suggesting that p57 may play an important role in liver carcinogenesis. However, the mechanism or oncogenic signal leading to p57 down-regulation in HCC remains to be determined. Herein, we demonstrated that Jab1/Csn5 expression is negatively correlated with p57 levels in HCC tissues. Kaplan-Meier analysis of tumor samples revealed that high Jab1/Csn5 expression with concurrent low p57 expression is associated with poor overall survival. The inverse pattern of Jab1 and p57 expression was also observed during carcinogenesis in a chemically induced rat HCC model. We also found that mechanistically, Jab1-mediated p57 proteolysis in HCC cells is dependent on 26S-proteasome inhibitors. We further demonstrated that direct physical interaction between Jab1 and p57 triggers p57 down-regulation, independently of Skp2 and Akt pathways, in HCC cells. These data suggest that Jab1 is an important upstream negative regulator of p57 and that aberrant expression of Jab1 in HCC could lead to a significant decrease in p57 levels and contribute to tumor cell growth. Furthermore, restoration of p57 levels induced by loss of Jab1 inhibited tumor cell growth and further increased cell apoptosis in HCC cells. Moreover, silencing Jab1 expression further enhanced the antitumor effects of cisplatin-induced apoptosis in HCC cells. Conclusion: Jab1-p57 pathway confers resistance to chemotherapy and may represent a potential target for investigational therapy in HCC. (HEPATOLOGY 2016;63:898-913) H epatocellular carcinoma (HCC) is the sixth most prevalent cancer in the world and is the third leading cause of cancer-related mortality. (1) Only 10% to 20% of HCC tumors can be removed completely by surgery in patients with HCC, and the reported cumulative 5-year recurrence rate after curative hepatectomy averages above 70% in both Eastern and Western medical centers. (2) At present, there is not only a lack of predictive and prognostic biomarkers in HCC patients but also a lack of effective therapeutic targets. Systemic treatment approaches are still the main option for patients with advanced HCC. Cisplatin-based regimens result in higher objective response rates than do non-cisplatin-based regimens in advanced HCC. However, the 15% response rate significantly limits the overall therapeutic benefit. (3) Abbreviations: CDK, cyclin-dependent kinase; HCC, hepatocellular carcinoma; siRNA, small interfering RNA; TCGA, the Cancer Genome Atlas; TGF-b, transforming growth factor b.

P57‐mediated autophagy promotes the efficacy of EGFR inhibitors in hepatocellular carcinoma

“…An increasing number of studies have shown that the expression of CIP/KIP family members is associated with anticancer treatment . Our previous studies suggested that p57 is expressed at a lower level in HCC tissues than in adjacent mucosae, and that decreased p57 levels are a predictor of poor outcomes in HCC patients . Additionally, our results revealed that the up‐regulation of p57 could improve the antitumour effects of cisplatin treatment in HCC cells .…”

“…It has been suggested that p57 is a tumour suppressor gene and plays vital roles in the proliferation and migration of tumour cells. Our previous studies have revealed that p57 downregulation results in accelerated growth in HCC cell lines by upregulating the levels of cyclin D1 and CDK2 and enhancing the activities of the CDK4/cyclin D1 and CDK2/cyclin E complexes. Furthermore, by transferring LIMK1 from the cytoplasm to the nucleus, p57 changes the level of phosphorylation of cofilin, thereby regulating HCC invasion and metastasis .…”

MicroRNA‐155‐5p promotes hepatocellular carcinoma progression by suppressing PTEN through the PI3K/Akt pathway

“…We determined the expressions of miR‐155‐5p and PTEN mRNA in a rat model of HCC induced by diethylnitrosamine/N‐nitrosomorpholine (DEN), which is similar to human HCC in terms of morphology and histology . The tumor types of all specimens were confirmed by two independent pathologists . Real‐time PCR results showed that miR‐155‐5p was significantly upregulated in 19 HCC tissues, but PTEN mRNA was downregulated in 14 HCC tissues from chemically‐induced HCC rats, compared with normal rats ( P < 0.05).…”

“…Eight‐week‐old male Sprague–Dawley rats were purchased from the Shanghai Experimental Animal Center and were housed in a pathogen‐free facility at the Animal Center of Xi'an Jiaotong University and the establishment of a rat model of chemically induced HCC was performed as previously described. The tumor types of all specimens were confirmed by two independent pathologists …”

Epithelial–mesenchymal transition induced cancer‐stem‐cell‐like characteristics in hepatocellular carcinoma

“…Tumor sphere numbers and volumes were estimated under a phase microscope at ×40 magnification every 3 days. ppm) containing water for 20 weeks (Guo et al, 2016). Saline was administered in control group rats (n = 15).…”