Xiujun Cai

Role of estrogen in hepatocellular carcinoma: is inflammation the key?

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and accounts for the third-leading cause of cancer-related deaths. Over the past decades, advances have been made in the field of surgery, but effective treatment of HCC is lacking. Due to a marked male predominance in morbidity and mortality in HCC patients, it has long been considered that sex hormones play a role in HCC development. Recently estrogen has been proven to exert protective effects against HCC through IL-6 restrictions, STAT3 inactivation and tumour-associated macrophage inhibition. While IL-6-dependent STAT3 activation is considered a key event in inflammation-induced liver cancer, the anti-inflammation effect of estrogen is well documented. The roles of the estrogen receptor and aromatase and interactions between microRNAs and estrogen in HCC have been investigated. In this review, we present a novel model to elucidate the mechanism of estrogen-mediated inhibition of HCC development through an anti-inflammation effect and provide new insights into the roles of estrogen in liver disease.

Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma

Sorafenib, an orally-available kinase inhibitor, is the only standard clinical treatment against advanced hepatocellular carcinoma. However, development of resistance to sorafenib has raised concern in recent years due to the high-level heterogeneity of individual response to sorafenib treatment. The resistance mechanism underlying the impaired sensitivity to sorafenib is still elusive though some researchers have made great efforts. Here, we provide a systemic insight into the potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma depending on abundant previous studies and reports.

Cisplatin enhances NK cells immunotherapy efficacy to suppress HCC progression via altering the androgen receptor (AR)-ULBP2 signals

The aim of this study is to investigate the influence of cisplatin on the efficacy of natural killer (NK) cells immunotherapy to suppress HCC progression, and provide valuable information on better application of cisplatin in clinical settings. By using in vitro cell cytotoxicity test and in vivo liver orthotopic xenograft mice model, we identified the role of cisplatin in modulating NK cells cytotoxicity. Luciferase report assay and chromatin immunoprecipitation assay were applied for mechanism dissection. Immunohistochemistry is performed for sample staining. We found cisplatin could enhance the efficacy of NK cells immunotherapy to better suppress HCC progression via altering the androgen receptor (AR)-UL16-binding protein 2 (ULBP2) signals both in vitro and in vivo. Mechanism dissection revealed that cisplatin could suppress AR expression via two distinct ways: increasing miR-34a-5p to suppress AR expression and altering the ubiquitination to accelerate the AR protein degradation. The suppressed AR might then function through up-regulating ULBP2, a natural-killer group 2 member D ligand, to enhance the cytotoxicity of NK cells. Together, these results indicated an unrecognized favoring effect of cisplatin in HCC treatment. By suppressing AR in HCC, cisplatin could up-regulate cytotoxicity of NK cells to better target HCC. This finding may provide a potential new approach to control HCC by combining traditional chemotherapy with immunotherapy.

Total laparoscopic left hepatectomy for primary hepatolithiasis: Eight-year experience in a single center

BACKGROUND Primary hepatolithiasis is prevalent in some Asian countries. Hepatectomy is a definitive treatment for this disease. Whether laparoscopic left hepatectomy (LLH) is suitable for primary hepatolithiasis remains controversial, because LLH is more challenging technically. The aim of this study was to evaluate the outcomes of LLH for primary hepatolithiasis in a single center. METHODS This retrospective study included 96 consecutive patients who underwent LLH for primary hepatolithiasis in the Sir Run Run Shaw Hospital from May 2005 to December 2012. In addition, 105 patients who met the same inclusion criteria for LLH but underwent open left hepatectomy (OLH) for hepatolithiasis during the same period were reviewed for comparison. The patient characteristics, operative features, postoperative course, residual stone rate, and recurrent stone rate were analyzed. RESULTS In the LLH group, 81 patients (84.4%) underwent total LLH and 15 (15.6%) were converted to open hepatectomy. The volume of intraoperative blood loss was less in the LLH than OLH group (383 ± 281 vs 554 ± 517 mL; P = .005). The intraoperative transfusion rate was also significantly lower in the LLH group (8.3% vs 30.5%; P < .001). There were no differences between the LLH and OLH groups in operation time, duration of postoperative hospitalization, postoperative complication rate, residual stone rate, or recurrent stone rate. CONCLUSION In experienced hands, total LLH is a safe, effective, and promising treatment for patients with hepatolithiasis.

ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis.

Significance About 40% of East Asians and over 500 million people worldwide carry a specific polymorphism, ALDH2*2, and exhibit “Asian flush” after alcohol drinking. We generated a mouse strain with this engineered polymorphism and demonstrated its resemblance to human carriers in terms of defective alcohol metabolism. With this model, we show that murine ALDH2*2 increases ALDH2 protein turnover and promotes chemical-induced liver tumor development. Importantly, ALDH2 is unstable in ALDH2*2 human liver samples and is significantly down-regulated in human liver tumors. Data from our mouse and clinical studies suggest that ALDH2 is a liver tumor suppressor and the ALDH2*2 polymorphism is a risk factor for liver cancer. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) in the liver removes toxic aldehydes including acetaldehyde, an intermediate of ethanol metabolism. Nearly 40% of East Asians inherit an inactive ALDH2*2 variant, which has a lysine-for-glutamate substitution at position 487 (E487K), and show a characteristic alcohol flush reaction after drinking and a higher risk for gastrointestinal cancers. Here we report the characterization of knockin mice in which the ALDH2(E487K) mutation is inserted into the endogenous murine Aldh2 locus. These mutants recapitulate essentially all human phenotypes including impaired clearance of acetaldehyde, increased sensitivity to acute or chronic alcohol-induced toxicity, and reduced ALDH2 expression due to a dominant-negative effect of the mutation. When treated with a chemical carcinogen, these mutants exhibit increased DNA damage response in hepatocytes, pronounced liver injury, and accelerated development of hepatocellular carcinoma (HCC). Importantly, ALDH2 protein levels are also significantly lower in patient HCC than in peritumor or normal liver tissues. Our results reveal that ALDH2 functions as a tumor suppressor by maintaining genomic stability in the liver, and the common human ALDH2 variant would present a significant risk factor for hepatocarcinogenesis. Our study suggests that the ALDH2*2 allele–alcohol interaction may be an even greater human public health hazard than previously appreciated.

Prognostic significance of E-cadherin expression in hepatocellular carcinoma: a meta-analysis.

Backgrounds Hepatocellular Carcinoma (HCC) is one of the most common malignancy of liver and HCC-related morbidity and mortality remains at high level. Researchers had investigated whether and how reduced E-cadherin expression impacted the prognosis of patients with HCC but the results reported by different teams remain inconclusive. Methods A systematic literature search was performed in all available databases to retrieve eligible studies and identify all relevant data, which could be used to evaluate the correlation between reduced E-cadherin expression and clinicopathological features and prognosis for HCC patients. A fixed or random effects model was used in this meta-analysis to calculate the pooled odds ratios (OR) and weighted mean differences (WMD) with 95% confidence intervals (CI). Results Total 2439 patients in thirty studies matched the selection criteria. Aggregation of the data suggested that reduced E-cadherin expression in HCC patients correlated with poor 1-, 3- and 5-year overall survival. The combined ORs were 0.50 (n = 13 studies, 95% CI: 0.37–0.67, Z = 4.49, P<0.00001), 0.39 (n = 13 studies, 95% CI: 0.28–0.56, Z = 5.12, P<0.00001), 0.40 (n = 11 studies, 95% CI: 0.25–0.64, Z = 3.82, P = 0.0001), respectively. Additionally, the pooled analysis denoted that reduced E-cadherin expression negatively impacts recurrence-free survival (RSF) with no significant heterogeneity. The pooled ORs for 1-, 3- and 5- year RSF affected by down-regulated E-cadherin were 0.73 (n = 6 studies, 95% CI: 0.54–1.00, Z = 1.95, P = 0.05), 0.70 (n = 6 studies, 95% CI: 0.52–0.95, Z = 2.32, P = 0.02), 0.66 (n = 5 studies, 95% CI: 0.48–0.90, Z = 2.64, P = 0.008). And what’s more, reduced E-cadherin expression tended to be significantly associated with metastasis (OR = 0.31, 95% CI: 0.16–0.60, Z = 3.50, P = 0.0005), vascular invasion (OR = 0.76, 95% CI: 0.59–0.98, Z = 2.14, P = 0.03), advanced differentiation grade (OR = 0.31, 95% CI: 0.21–0.45, Z = 6.04, P<0.00001) and advanced TMN stage (T3/T4 versus T1/T2) (OR = 0.61,95% CI:0.38–0.98, Z = 2.05, P = 0.04). Conclusions Reduced E-cadherin expression indicates a poor prognosis for patients with HCC, and it may have predictive potential for prognosis of HCC patients.

Chk1-induced CCNB1 overexpression promotes cell proliferation and tumor growth in human colorectal cancer

The high morbidity and mortality of colorectal cancer pose a significant public health problem worldwide. Here we assessed the pro-cancer efficacy and mechanism of action of CCNB1 in different colorectal cancer cells. We provided evidence that CCNB1 mRNA and protein level were upregulated in a subset of human colorectal tumors, and positively correlated with Chk1 expression. Repression of Chk1 caused a significant decrease in cell proliferation and CCNB1 protein expression in colorectal cancer cells. Furthermore, downregulation of CCNB1 impaired colorectal cancer proliferation in vitro and tumor growth in vivo. Specifically, suppression of CCNB1 caused a strong G2/M phase arrest in both HCT116 and SW480 cells, interfering with the expression of cdc25c and CDK1. Additionally, CCNB1 inhibition induced apoptotic death in certain colorectal cancer cells. Together, these results suggest that CCNB1 is activated by Chk1, exerts its oncogenic role in colorectal cancer cells, and may play a key role in the development of a novel therapeutic approach against colorectal cancer.

Targeting Androgen Receptor (AR)→IL12A Signal Enhances Efficacy of Sorafenib plus NK Cells Immunotherapy to Better Suppress HCC Progression

Gender disparity has long been considered as a key to fully understand hepatocellular carcinoma (HCC) development. At the same time, immunotherapy related to IL12 still need more investigation before being applied in clinical settings. The aim of this study is to investigate the influence of the androgen receptor (AR) on natural killer (NK) cell–related innate immune surveillance in liver cancer, and provide a novel therapeutic approach to suppress HCC via altering IL12A. By using in vitro cell cytotoxicity test and in vivo liver orthotopic xenograft mouse model, we identified the role of AR in modulating NK cell cytotoxicity. Luciferase report assay and chromatin immunoprecipitation assay were applied for mechanism dissection. IHC was performed for sample staining. Our results showed AR could suppress IL12A expression at the transcriptional level via direct binding to the IL12A promoter region that resulted in repressing efficacy of NK cell cytotoxicity against HCC, and sorafenib treatment could enhance IL12A signals via suppressing AR signals. These results not only help to explain the AR roles in the gender disparity of HCC but also provide a potential new therapy to better suppress HCC via combining sorafenib with NK cell–related immunotherapy. Mol Cancer Ther; 15(4); 731–42. ©2016 AACR.

Clinical implication of Keap1 and phosphorylated Nrf2 expression in hepatocellular carcinoma

In this paper, variation tendency of phosphorylated Nrf2, as the activated form of native Nrf2, was studied in 107 primary hepatocellular carcinoma (HCC) specimens treated by curative hepatectomy. Moreover, the coexpression of oxidative stress markers Keap1 and pNrf2, and their association with pathological features were also evaluated based on those specimens. The results showed that preserved cytoplasmic Keap1 expression of cancer cells was observed in 59 HCCs, while reduced Keap1 expression was determined in remaining 48 ones. With regarding to nuclear pNrf2 expression, 75 HCCs were defined as high and the other 32 ones as low. There was a significant association between Keap1 and pNrf2 expression in HCCs. Higher pNrf2 expression was observed, at a more substantial proportion, in those specimens with reduced Keap1 expression, compared to those with preserved Keap1 expression. The subset with higher pNrf2 and reduced Keap1 expression was defined as pNrf2+ Keap1−. According to the analysis of prognosis, this subset was significantly associated with poor 5‐year overall survival and worse disease‐free survival in HCCs, indicating that pNrf2 and Keap1 were two‐functional biomolecules, not only the oxidative stress markers but also biomarkers for prognosis of HCCs.

Cyclin b1 suppresses colorectal cancer invasion and metastasis by regulating e-cadherin.

Cyclin B1, a mitotic cyclin, has been implicated in malignances. However, its contribution to colorectal cancer invasion and metastasis are still not well understood. Here, we demonstrated that the invasion and metastasis of colorectal cancer is regulated by Cyclin B1. Overexpression of Cyclin B1 was observed in colorectal cancer tissues, but this elevated expression was negatively associated with lymph node metastasis, distant metastasis stage, and TNM stage. The Kaplan-Meier survival analysis proved that low Cyclin B1 expression was associated with poor overall survival of patients with colorectal cancer. Inhibition of Cyclin B1 in colorectal cancer cells enhanced the cell migration and invasion of three different colorectal cancer cell lines. In studying the possible mechanism by which Cyclin B1 suppresses colorectal cancer invasion and metastasis, we observed that suppression of Cyclin B1 decreased the expression of E-cadherin protein level. Our findings suggest that Cyclin B1 could suppress the invasion and metastasis of colorectal cancer cells through regulating E-cadherin expression, which enables the development of potential intervention strategies for colorectal cancer.