SCYL3, as a novel binding partner and regulator of ROCK2, promotes hepatocellular carcinoma progression.

Background & Aims: SCY1-like pseudokinase 3 (SCYL3) was identified as a binding partner of ezrin, implicating it in metastasis. However, the clinical relevance and functional role of SCYL3 in cancer remain uncharacterized. In this study, we aimed to elucidate the role of SCYL3 in the progression of hepatocellular carcinoma (HCC). Methods: The clinical significance of SCYL3 in HCC was evaluated in publicly available datasets and by qPCR analysis of an in-house HCC cohort. The functional significance and mechanistic consequences of SCYL3 were examined in SCYL3-knockdown/overexpressing HCC cells. In vivo tumor progression was evaluated in Tp53 KO/c-Myc OE mice using the sleeping beauty transposon system. Potential downstream pathways were investigated by co-immunoprecipitation, western blotting analysis and immunofluorescence staining. Results: SCYL3 is often overexpressed in HCC; it is preferentially expressed in metastatic human HCC tumors and is associated with worse patient survival. Suppression of SCYL3 in HCC cells attenuated cell proliferation and migration as well as in vivo metastasis. Intriguingly, endogenous SCYL3 overexpression increased tumor development and metastasis in Tp53 KO/c-Myc OE mice. Mechanistic investigations revealed that SCYL3 physically binds and regulates the stability and transactivating activity of ROCK2 (Rho kinase 2) via its C-terminal domain, leading to the increased formation of actin stress fibers and focal adhesions. Conclusions: These findings reveal that SCYL3 plays a critical role in promoting the progression of HCC and have implications for developing new therapeutic strategies to tackle metastatic HCC. Impact and implications: SCYL3 was first reported to be a binding partner of a metastasis-related gene, ezrin. To date, the clinical relevance and functional role of SCYL3 in cancer remain uncharacterized. Herein, we uncover its crucial role in liver cancer progression. We show that it physically binds and regulates the stability and transactivating activity of ROCK2 leading to HCC tumor progression. Our data provide mechanistic insight that SCYL3-mediated ROCK2 protein stability plays a pivotal role in growth and metastasis of HCC cells. Targeting SCYL3/ROCK2 signaling cascade may be a novel therapeutic strategy for treatment of HCC patients.

[Clinical significance of monitoring coagulation- and fibrinolysis-related indexes during catheter-directed thrombolysis for acute lower-extremity deep venous thrombosis].

OBJECTIVE: To investigate the patterns of changes in serum levels of of D-dimer, fibrinogen (FIB) and fibrin degradation product (FDP) during catheter-directed thrombolysis (CDT) in patients with acute lower-extremity deep venous thrombosis (DVT) and explore their clinical significance. METHODS: From June, 2014 to June, 2015, 50 patients with acute lower-extremity DVT received CDT. The serum concentrations of D-dimer, FIB and FDP were measured before, during and after CDT in all the subjects, with 50 healthy subjects serving as the control group. RESULTS: Compared with the control group, the patients in DVT group showed significantly increased serum levels of D-dimer (29.17±38.67 vs 0.21 ±0.27 µg/mL), FIB (3.66±0.95 vs 3.32±0.65 g/L) and FDP (76.14±131.48 vs 1.08±0.73 µg/mL) before CDT (P<0.05). Based on the effect of CDT, the patients with DVT were divided into recanalization group (n=34) and failed recanalization group (n=16), and the patients with recanalization had significantly increased serum concentration of D-dimer and FDP (P<0.05) and decreased FIB level (P<0.05) compared with those with failed recanalization at 24 h of CDT. D-dimer, FDP, and FIB showed no significant changes in the patients with failed recanalization after the procedure (P>0.05). Correlation analysis showed that serum D-dimer (r=0.66, P<0.05) and FDP (r=0.50, P<0.05) at 24 h of the procedure were positively correlated with the outcomes of CDT. CONCLUSION: Serum levels of D-dimer, FIB and FDP are important indicators for evaluating and predicting the effectiveness of CDT in patients with acute DVT.

Transjugular intrahepatic portosystemic shunt with covered stents for hepatocellular carcinoma with portal vein tumor thrombosis.

AIM: To evaluate transjugular intrahepatic portosystemic shunt (TIPS) with covered stents for hepatocellular carcinoma (HCC) with main portal vein tumor thrombus (PVTT). METHODS: Eleven advanced HCC patients (all male, aged 37-78 years, mean: 54.3 ± 12.7 years) presented with acute massive upper gastrointestinal bleeding (n = 9) or refractory ascites (n = 2) due to tumor thrombus in the main portal vein. The diagnosis of PVTT was based on contrast-enhanced computed tomography and color Doppler sonography. The patients underwent TIPS with covered stents. Clinical characteristics and average survival time of 11 patients were analyzed. Portal vein pressure was assessed before and after TIPS. The follow-up period was 2-18 mo. RESULTS: TIPS with covered stents was successfully completed in all 11 patients. The mean portal vein pressure was reduced from 32.0 to 11.8 mmHg (t = 10.756, P = 0.000). Gastrointestinal bleeding was stopped in nine patients. Refractory ascites completely disappeared in one patient and was alleviated in another. Hepatic encephalopathy was observed in six patients and was resolved with drug therapy. During the follow-up, ultrasound indicated the patency of the shunt and there was no recurrence of symptoms. Death occurred 2-14 mo (mean: 5.67 mo) after TIPS in nine cases, which were all due to multiple organ failure. In the remaining two cases, the patients were still alive at the 16- and 18-mo follow-up, respectively. CONCLUSION: TIPS with covered stents for HCC patients with tumor thrombus in the main portal vein is technically feasible, and short-term efficacy is favorable.