Bai Ji

MicroRNA-133a functions as a tumor suppressor by targeting IGF-1R in hepatocellular carcinoma

MicroRNAs (miRNAs) are a class of small non-coding RNAs and have critical roles in tumorigenesis and metastasis. A growing body of evidence showed that microRNA-133a (miR-133a) was downregulated and played tumor suppressor roles in gastric, colorectal, bladder, and lung cancer. However, the role and underlying molecular mechanism of miR-133a in hepatocellular carcinoma (HCC) remain unclear. In this study, we analyzed the expression of miR-133a in HCC tissues and HCC cell lines. We find that miR-133a was downregulated in HCC tissues and cell lines and that miR-133a expression negatively correlated with tumor differentiation (P < 0.01), TNM stage (P < 0.01), and lymph node metastasis (P < 0.01). Then, functional studies demonstrate that restoration of miR-133a in HepG2 cells significantly suppressed proliferation, colony formation, migration, and invasion, induced cell cycle arrest at G0/G1 stage and cell apoptosis in vitro, and decreased tumor size and weight in a nude mouse HepG2 xenograft model. Using bioinformatics method and dual luciferase assays identified insulin-like growth factor 1 receptor (IGF-1R) as a direct target of miR-133a in HCC cells. Furthermore, overexpression of miR-133a inhibited activation AKT and ERK signal pathway, which contributed to suppression of HCC cell growth. These findings suggest that miR-133a may act as a tumor suppressor and inhibited survival of HCC cells by targeting IGF-1R.

Abdominal Multiple Splenosis Mimicking Liver and Colon Tumors: A Case Report and Review of the Literature

Splenosis is not an uncommon disease. However, it is often misdiagnosed as malignant tumors, and then the patients underwent unnecessary operations. Unfortunately, it is very difficult to diagnose it prior to operation. We report a rare case of a 49-year-old female patient with liver and colon splenosis, misdiagnosed as liver and colon tumors, and summarize experience how to diagnose it preoperatively according to literatures. We come to conclusion that in patients who ever underwent splenectomy especially owning to trauma, and were found mass in abdomen, clinicians must consider the existence of splenosis, and take some measures, such as scintigraphy with (99m) Tc labelled heat-denatured erythrocyte rather than biopsy, to diagnose it correctly to prevent unnecessary operations.

miR‑222 regulates sorafenib resistance and enhance tumorigenicity in hepatocellular carcinoma

The miR‑222 cluster has been demonstrated to function as oncomiR in human hepatocellular carcinoma (HCC). miR‑222 confers chemotherapy drug resistance in various cancers, including HCC. However, the effects and mechanisms by which miR‑222 regulates liver tumorigenicity and confers sorafenib (SOR) resistance remain unclear. Here we first investigated the miR‑222 effect on proliferation, cell cycle, apoptosis, migration and invasion of HCC. Our results demonstrated that miRNA inhibitors specially targeting miR‑222 significantly suppressed cellular proliferation, migration, invasion and G1/S transition of the cell cycle, and induced cell apoptosis in HepG2 cells. In addition, we investigated whether miR‑222 confers SOR resistance in HepG2 cells to explore it roles in acquisition of drug resistance. The results showed that miR‑222 inhibitors induced sensitivity to the antitumor effect of sorafenib in human HepG2 cells. Importantly, our study also showed that miR‑222 could regulate the expression of phosphorylation PI3K and AKT, which might contribute to miR‑222 conferred SOR resistance in HepG2 cells. In conclusion, this study demonstrates that miR‑222 can promote cell proliferation, migration and invasion, and decrease cell apoptosis, as well as enhance the resistance of HCC cells to sorafenib miR‑222 through activating the PI3K/AKT signaling pathway.

A disintegrin and metalloprotease (ADAM)10 is highly expressed in hepatocellular carcinoma and is associated with tumour progression

Objective A disintegrin and metalloprotease (ADAM)10 has been implicated in the progression of various solid tumours. Little is known, however, about its role in hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the protein and transcript level expression of ADAM10 in HCC patients. Methods Samples of HCC and adjacent noncancerous liver tissue were taken during liver resection surgery. Immunostaining was used to measure ADAM10 protein expression levels and quantitative reverse– transcription polymerase chain reaction was used to measure ADAM10 mRNA expression levels. Levels of ADAM10 were compared, and a survival analysis undertaken. Results In total, 98 HCC patient samples were studied. There were significant associations between protein levels of ADAM10 and tumour grade, amount of tumour differentiation, tumour size and the presence of metastasis. Furthermore, ADAM10 protein expression was significantly associated with shortened patient survival. Conclusions ADAM10 is strongly expressed in a large proportion of HCC cases, which is in agreement with findings in other tumour entities. Expression of ADAM10 may serve as a useful molecular marker for HCC.

Silencing ADAM10 inhibits the in vitro and in vivo growth of hepatocellular carcinoma cancer cells

A disintegrin and metalloprotease 10 (ADAM10) is a transmembrane protein associated with metastasis in a number of types of cancer. Little is known, however, regarding the role of ADAM10 in hepatocellular carcinoma (HCC). The aim of the present study was to evaluate whether downregulation of ADAM10 effects HCC cell proliferation, cell cycle, cell migration and cell invasion. A recombinant small hairpin RNA expression vector carrying ADAM10 was constructed and then transfected into the HepG2 human HCC cell line. In vitro cell proliferation, cell cycle, cell migration and cell invasion, and in vivo tumor growth were determined following the downregulation of ADAM10 by RNA interference. The results revealed that downregulation of ADAM10 expression in HepG2 tumor cells using the RNA silencing approach significantly suppressed cell proliferation, cell migration and cell invasion in vitro, and tumor growth in vivo. Furthermore, ADAM10 silencing was able to significantly reduce constitutive phosphorylation of phosphoinositide 3-kinase (PI3K) and Akt, which implies that ADAM10 is, at least partially, involved in the activation of the PI3K/Akt signaling pathway. These results suggest that ADAM10 is important in regulating the proliferation and metastasis of HCC. Thus, ADAM10 is a promising therapeutic target for the prevention of tumor metastases in HCC.

Targeting the PD-L1/DNMT1 axis in acquired resistance to sorafenib in human hepatocellular carcinoma

Molecule-targeted therapy, such as sorafenib, is one of the effectively therapeutic options for advanced hepatocellular carcinoma (HCC). However, acquired resistance to sorafenib has been found in some HCC patients, resulting in poor prognosis. It is reported that PD-L1 and DNA methyltransferases (DNMTs) contribute to drug resistance. In this study, by inducing sorafenib-resistant HCC cell lines, we investigated their molecular and functional characteristics. Our data indicated that highly upregulated DNMT1 was positively correlated with PD-L1 overexpression in sorafenib-resistant HCC cells. We demonstrate that PD-L1 regulate DNMT1 through STAT3 signaling pathway. Knockdown of PD-L1 induced DNMT1-dependent DNA hypomethylation and restored the expression of methylation-silenced CDH1. Moreover, inactivation of NFκB blocked PD-L1/STAT3/DNMT1 pathway in sorafenib-resistant HCC cells. Functionally, genetic or pharmacological disruption of PD-L1 or/and DNMT1 sensitize HCC resistance to sorafenib. Importantly, dual inactivation of PD-L1 and DNMT1 by their inhibitor synergistically disrupts the colony formation of sorafenib-resistant HCC cells. These results demonstrate that targeting NFκB/PDL1/STAT3/DNMT1 axis is a new therapeutic strategy for preventing or overcoming the acquired resistance to sorafenib in HCC patients.

Comparison of iodine-125 seed implantation and pancreaticoduodenectomy in the treatment of pancreatic cancer.

Objective: This retrospective study compared the advantages and disadvantages of iodine-125 (125I) seed implantation and pancreaticoduodenectomy (PD) in the treatment of pancreatic cancer. Methods: Patients with diagnosed pancreatic cancer who were treated with 125125I seed implantation (30 patients) or PD (30 patients) in our hospital were evaluated for operative time, bleeding, liver function, time to first bowel movement and normal diet, survival, and medical costs. Results: Compared with patients who underwent PD, those given 125I seed implantation had significantly shorter operative time, less bleeding, higher albumin, shorter periods to bowel movement and normal diet, lower risk of complications, and lower medical costs (P < 0.001, each). The difference of bilirubin level, time to feeding, and median survival were not significant statistically between two treatment grouops. Conclusion: For pancreatic cancer patients for whom PD is not appropriate or who refuse PD, 125I seed implantation is a good option.

Hem-o-lok clip found in common bile duct after laparoscopic cholecystectomy and common bile duct exploration: a clinical analysis of 8 cases.

Currently laparoscopic cholecystectomy (LC) and common bile duct exploration (LCBDE) has become the standard surgical procedure for cholecystolithiasis and choledocholithiasis. During the operation cystic duct and vessels are usually controlled by Hem-o-lok clips. However, recently we found clips dropping into CBD in 8 patients during fiberoptic choledochoscope 2-3 months after operation. Therefore, there is risk that clip can migrate during postoperative period, which probably lead to hemorrhage and bile leakage after LC if this occurs within postoperative few days, or even cause recurrent stone in CBD. So, using of Hem-o-lok clips may be not a safe method to control vessels and cystic duct during LC. To our knowledge, this condition has not previously been reported. In our view, other more effective and safe method ligating cystic duct and gallbladder vessels, such as effective and convenient thread knotting method, should be investigated.

Synergistic effects of co-expression plasmid‑based ADAM10-specific siRNA and GRIM-19 on hepatocellular carcinoma in vitro and in vivo

A disintegrin and metalloproteinase 10 (ADAM10) has been demonstrated to correlate with hepatocellular carcinoma (HCC) grade and clinical outcome and its potential as a target for HCC therapy has been established. Gene associated with retinoid-interferon-induced mortality 19 (GRIM-19), a signal transducer and activator of transcription 3 (Stat3)-inhibitory protein, was identified as a potential tumor suppressor associated with growth inhibition and cell apoptosis. In the present study, we investigated whether a combined treatment with ADAM10-specific siRNA and GRIM19 gene could have an enhanced anticancer effectiveness on HCC in vitro and in vivo. We developed a dual expression plasmid that co-expressed ADAM10-specific siRNA and GRIM19, to evaluate its effects on HCC growth. Our results showed that simultaneous expression of ADAM10-specific siRNA and GRIM19 (pSi-ADAM10-GRIM19) in HepG2 cancer cells significantly inhibited the proliferation, migration and invasion, and induced cell apoptosis in vitro, and it also suppressed tumor growth in a nude mouse model when compared to the controls, either ADAM10-specific siRNA or GRIM-19 alone. In summary, our data demonstrated that a combined strategy of co-expressed ADAM10-specific siRNA and GRIM19 synergistically and more effectively suppressed HCC tumor growth, and has therapeutic potential for the treatment of HCC.

Anterior Versus Posterolateral Approach for Total Laparoscopic Splenectomy: A Comparative Study

Objective: Although the anterior approach is normally used for elective laparoscopic splenectomy (LS), the posterolateral approach may be superior. We have retrospectively compared the effectiveness and safety of these approaches in patients with non-severe splenomegaly scheduled for elective total LS. Methods: Patients with surgical spleen disorders scheduled for elective LS between March 2005 and June 2011 underwent laparoscopic splenic mobilization via the posterolateral or anterior approach. Main outcome measures included operation time, intraoperative blood loss, frequency of postoperative pancreatic leakage, and length of hospital stay. Results: During the study period, 203 patients underwent LS, 58 (28.6%) via the posterolateral and 145 (71.4%) via the anterior approach. Three patients (1.5%) required conversion to laparotomy due to extensive perisplenic adhesions. The posterolateral approach was associated with significantly shorter operation time (65.0 ± 12.3 min vs. 95.0 ± 21.3 min, P < 0.01), reduced intraoperative blood loss (200.0 ± 23.4 mL vs. 350.0 ± 45.2 mL, P < 0.01), and shorter hospital stay (5.0 ± 2.0 d vs. 9.0 ± 3.0 d, P < 0.01) than the anterior approach. The frequency of pancreatic leakage was slightly lower in patients undergoing LS via the posterolateral than the anterior approach (0.0% vs. 3.4%, P > 0.05) Conclusions: The posterolateral approach is more effective and safer than the anterior approach in patients without severe splenomegaly (< 30 cm).