Efficacy and safety of laparoscopic common bile duct exploration with primary closure and intraoperative endoscopic nasobiliary drainage for choledocholithiasis combined with cholecystolithiasis.

BACKGROUND: The need for intraoperative endoscopic nasobiliary drainage during laparoscopic cholecystectomy and laparoscopic common bile duct exploration with primary closure is controversial in the treatment of cholecystolithiasis combined with choledocholithiasis. The aim of this study was to evaluate the safety and efficacy of laparoscopic cholecystectomy + laparoscopic common bile duct exploration + intraoperative endoscopic nasobiliary drainage + primary closure (LC + LCBDE + IO-ENBD + PC). The safety of different intubation methods in IO-ENBD was also evaluated. METHOD: From January 2018 to January 2022, 168 consecutive patients with cholecystolithiasis combined with choledocholithiasis underwent surgical treatment in our institution. Patients were divided into two groups: group A (n = 96) underwent LC + LCBDE + IO-ENBD + PC and group B (n = 72) underwent LC + LCBDE + PC. Patient characteristics, perioperative indicators, complications, stone residual, and recurrence rates were analyzed. Group A was divided into two subgroups. In group A1, the nasobiliary drainage tube was placed in an anterograde way, and in group A2, nasobiliary drainage tube was placed in an anterograde-retrograde way. Perioperative indicators and complications were analyzed between subgroups. RESULTS: No mortality in the two groups. The operation success rates in groups A and B were 97.9% (94/96) and 100% (72/72), respectively. In group A, two patients were converted to T-tube drainage. The stone clearance rates of group A and group B were 100% (96/96) and 98.6% (71/72), respectively. Common bile duct diameter was smaller in group A [10 vs. 12 mm, P < 0.001] in baseline data. In perioperative indicators, group A had a longer operation time [165 vs.135 min, P < 0.001], but group A had a shorter hospitalization time [10 vs.13 days, P = 0.002]. The overall complications were 7.3% (7/96) in group A and 12.5% (9/72) in group B. Postoperative bile leakage was less in group A [0% (0/96) vs. 5.6% (4/72), P = 0.032)]. There were no residual and recurrent stones in group A. And there were one residual stone and one recurrent stone in group B (all 1.4%). The median follow-up time was 12 months in group A and 6 months in group B. During the follow-up period, 2 (2.8%) patients in group B had a mild biliary stricture. At subgroup analysis, group A1 had shorter operation time [150 vs. 182.5 min, P < 0.001], shorter hospitalization time [9 vs. 10 days, P = 0.002], and fewer patients with postoperative elevated pancreatic enzymes [32.6% (15/46) vs. 68% (34/50), P = 0.001]. CONCLUSION: LC + LCBDE + IO-ENBD + PC is safer and more effective than LC + LCBDE + PC because it reduces hospitalization time and avoids postoperative bile leakage. In the IO-ENBD procedure, the antegrade placement of the nasobiliary drainage tube is more feasible and effective because it reduces the operation time and hospitalization time, and also reduces injury to the duodenal papilla.

Ubiquitin-specific protease 1 acts as an oncogene and promotes lenvatinib efficacy in hepatocellular carcinoma by stabilizing c-kit.

INTRODUCTION AND OBJECTIVES: Ubiquitin-specific proteases (USPs) act as proto-oncogenes or tumor suppressors in a wide variety of cancers. In this study, we intended to explore the role of USP1 in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The clinical significance of USP1 in HCC was analyzed based on The Cancer Genome Atlas (TCGA) data and immunohistochemical staining. siRNAs and lentivirus were used to knock down and overexpress indicated genes, respectively. qRT-PCR and immunoblotting were performed to examine mRNA and protein expression, respectively. CCK8, colony formation and PI/Annexin V-APC staining were performed to examine cellular function. Immunoprecipitation, coomassie blue staining, mass spectrum and immunoblotting were conducted to evaluate the interaction between USP1 and c-kit. RESULTS: USP1 was over-expressed in HCC patients. Patients with high expression of USP1 had shorter overall and disease free survival than those with low expression of USP1. Functional results showed that USP1 was critical for HCC cell growth and proliferation. Immunoprecipitation and immunoblotting results suggested that USP1 interacted with c-kit and promoted the stability of c-kit, which is an important target of lenvatinib in HCC. Knockdown of c-kit reversed the oncogenic function of USP1 on HCC cell growth. Lastly, USP1 upregulation conferred higher sensitivity of HCC cells to lenvatinib treatment. CONCLUSIONS: Our study demonstrated that USP1 acted as an oncogene in HCC. It also promoted lenvatinib efficacy by stabilizing c-kit.

Co-expression analysis and ceRNA network reveal eight novel potential lncRNA biomarkers in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer in the world, with a high degree of malignancy and recurrence. The influence of the ceRNA network in tumor on the biological function of liver cancer is very important, It has been reported that many lncRNA play a key role in liver cancer development. In our study, integrated data analysis revealed potential eight novel lncRNA biomarkers in hepatocellular carcinoma. METHODS: Transcriptome data and clinical data were downloaded from the The Cancer Genome Atlas (TCGA) data portal. Weighted gene co-expression network analysis was performed to identify the expression pattern of genes in liver cancer. Then, the ceRNA network was constructed using transcriptome data. RESULTS: The integrated analysis of miRNA and RNAseq in the database show eight novel lncRNAs that may be involved in important biological pathways, including TNM and disease development in liver cancer. We performed function enrichment analysis of mRNAs affected by these lncRNAs. CONCLUSIONS: By identifying the ceRNA network and the lncRNAs that affect liver cancer, we showed that eight novel lncRNAs play an important role in the development and progress of liver cancer.

Identification of metabolism-associated pathways and genes involved in male and female liver cancer patients.

Hepatocellular carcinoma (HCC) is a major type of primary liver cancer. HCC is influenced by sex and multiple metabolic abnormalities. The present study aimed to compare the overall metabolic changes between male and female HCC patients and identify key metabolic genes. Metabolic genes and pathways were identified based on analyses of publicly available data. Differential expression analysis, gene set enrichment analysis, survival analysis and transcriptional regulation analysis were employed to explore sex differences and identify key metabolic genes in HCC. The results suggested that female patients had more severe metabolic gene expression abnormalities and pathway deregulation than male patients. This study identified 9 key metabolic genes, and only upregulated ALDH1A2 independently increased overall survival risk in patients. Bioinformatic analyses suggest that upregulated GATA3 and TAL1 activate ALDH1A2 and then disrupt amino acid and carbohydrate metabolism, which may increase the risk of HCC. This study identified a novel contribution of upregulated ALDH1A2 to HCC. Future studies are needed to elucidate the potential metabolic mechanism of the role of ALDH1A2 in HCC.

Long non-coding RNA snaR is involved in the metastasis of liver cancer possibly through TGF-ß1.

It was previously demonstrated that the long non-coding RNA (lncRNA) small NF90-associated RNA (snaR) served an oncogenic role in human colon cancer, although its roles in other types of cancer remain unknown. To investigate the potential involvement of lncRNA snaR in hepatocellular carcinoma (HCC), expression of snaR in liver biopsies and plasma of patients with HCC and healthy controls was detected by reverse transcription-quantitative polymerase chain reaction. ELISA was used to determine the protein expression levels of transforming growth factor-ß1 (TGF-ß1). A snaR expression vector was transfected into HCC cells, and the effects on cell migration and invasion were analyzed by Transwell migration and Matrigel invasion assays, respectively. The protein expression levels of TGF-ß1 in HCC cells were detected by western blotting. The expression of snaR and TGF-ß1 was significantly increased in the patients with HCC compared with the healthy controls. The plasma expression levels of snaR and TGF-ß1 were positively correlated in patients with HCC; however, not in healthy controls. snaR overexpression significantly promoted cancer cell migration and invasion, and additionally increased TGF-ß1 expression. Treatment with TGF-ß1 did not significantly affect snaR expression. A TGF-ß1 inhibitor attenuated the effects of snaR overexpression in cancer cell migration and invasion. snaR may promote the metastasis of liver cancer through TGF-ß1.

Discs large homolog 5 decreases formation and function of invadopodia in human hepatocellular carcinoma via Girdin and Tks5.

Invadopodium formation is a crucial early event of invasion and metastasis of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying regulation of invadopodia remain elusive. This study aimed to investigate the potential role of discs large homolog 5 (Dlg5) in invadopodium formation and function in HCC. We found that Dlg5 expression was significantly lower in human HCC tissues and cell lines than adjacent nontumor tissues and liver cells. Lower Dlg5 expression was associated with advanced stages of HCC, and poor overall and disease-free survival of HCC patients. Dlg5-silencing promoted epithelial-mesenchymal transition, invadopodium formation, gelatin degradation function, and invadopodium-associated invasion of HepG2 cells. In contrast, Dlg5 overexpression inhibited epithelial-mesenchymal transition, functional invadopodium formation, and invasion of SK-Hep1 cells. Both Girdin and Tks5, but not the Tks5 nonphosphorylatable mutant, were responsible for the enhanced invadopodium formation and invasion of Dlg5-silenced HepG2 cells. Furthermore, Dlg5 interacted with Girdin and interfered with the interaction of Girdin and Tks5. Dlg5 silencing promoted Girdin and Tks5 phosphorylation, which was abrogated by Girdin silencing and rescued by inducing shRNA-resistant Girdin expression. Moreover, Dlg5 overexpression significantly inhibited HCC intrahepatic and lung metastasis in vivo. Taken together, our data indicate that Dlg5 acts as a novel regulator of invadopodium-associated invasion via Girdin and by interfering with the interaction between Girdin and Tks5, which might be important for Tks5 phosphorylation in HCC cells. Conceivably, Dlg5 may act as a new biomarker for prognosis of HCC patients.

Scutellarin suppresses migration and invasion of human hepatocellular carcinoma by inhibiting the STAT3/Girdin/Akt activity.

Scutellarin is an active flavone from Erigeron breviscapine (vant) Hand Mass. This study aimed to investigate the potential role of scutellarin in migration and invasion of human hepatocellular carcinoma (HCC) cells and its possible mechanism. In comparison with the vehicle-treated controls, treatment with scutellarin (50 mg/kg/day) for 35 days significantly mitigated the lung and intrahepatic metastasis of HCC tumors in vivo. Scutellarin treatment significantly reduced HepG2 cell viability in a dose-dependent manner, and inhibited migration and invasion of HCC cells in vitro. Scutellarin treatment significantly reduced STAT3 and Girders of actin filaments (Girdin) expression, STAT3 and Akt phosphorylation in HCC cells. Introduction of STAT3 overexpression restored the scutellarin-downregulated Girdin expression, Akt activation, migration and invasion of HCC cells. Furthermore, induction of Girdin overexpression completely abrogated the inhibition of scutellarin on the Akt phosphorylation, migration and invasion of HCC cells. Scutellarin can inhibit HCC cell metastasis in vivo, and migration and invasion in vitro by down-regulating the STAT3/Girdin/Akt signaling.