Ubiquitin ligase MARCH8 promotes the malignant progression of hepatocellular carcinoma through PTEN ubiquitination and degradation.

Membrane-associated ring-CH-type finger 8 (MARCH8) belongs to the MARCH family of membrane-bound E3 ubiquitin ligases. The N-terminus of MARCH family members contains the C4HC3 RING-finger domain, which can bind to E2 ubiquitin-conjugating enzymes, ubiquitinate substrate proteins, and thereby promote protein degradation through the proteasome pathway. The aim of this study was to determine the role of MARCH8 in hepatocellular carcinoma (HCC). We first analyzed the clinical relevance of MARCH8 based on The Cancer Genome Atlas database. Immunohistochemical staining was used to detect MARCH8 expression in human HCC samples. Migration and invasion assays were conducted in vitro. Cell apoptosis and cell cycle distribution were analyzed by flow cytometry. The expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-related markers was evaluated in HCC cells through Western blot analysis. MARCH8 was highly expressed in human HCC tissues, and its high expression was inversely correlated with patients' survival. Disrupting MARCH8 expression significantly inhibited the proliferation, migration, and cell cycle progression of HCC cells, while also promoting their apoptosis. In contrast, the overexpression of MARCH8 significantly enhanced cell proliferation. Mechanistically, our results showed that MARCH8 interacted with PTEN and suppressed the protein stability of PTEN by enhancing its ubiquitination level via the proteasome. MARCH8 also activated AKT in HCC cells and tumors. In vivo, overexpression of MARCH8 could promote the growth of hepatic tumors through the AKT pathway. MARCH8 may promote the malignant progression of HCC by promoting the ubiquitination of PTEN, thereby relieving the inhibitory effect of PTEN on the malignant phenotype of HCC cells.

[Solid Tumors With Cold Agglutinins:Report of Two Cases and Literature Review].

Cold agglutinins(CA),autoantibodies against the antigen I or i on the surface of red blood cells,are mainly of IgM class,and the majority have κ light chains.They can lead to red blood cell agglutination at decreased body temperature and are usually associated with infections,drug reactions,autoimmune diseases,and hematological malignancies.However,solid tumors with CA are rare.We reported two cases of CA in the peripheral blood of patients with solid tumors.Peripheral complete blood cell count of the patients at admission showed reduced erythrocyte count and hematocrit,mismatching between erythrocyte count and hemoglobin,abnormally elevated levels of mean corpuscular hemoglobin and mean cell hemoglobin concentration.Peripheral blood smear showed erythrocyte aggregation.After the sample was preheated at 37 ℃ for 30 min,the reversibility of red blood cell aggregation was observed,and the erythrocyte parameters were corrected.

Laparoscopic caudate lobectomy: a multicenter, propensity score-matched report of safety, feasibility, and early outcomes.

BACKGROUND: Caudate lobectomy via laparoscopic surgery has rarely been described. This multicenter, propensity score-matched study was performed to assess the safety and efficacy of laparoscopic caudate lobectomy (LCL). METHODS: A multicenter retrospective study was performed including all patients who underwent LCL and open caudate lobectomy (OCL) in four institutions from January 2013 to December 2018. In total, 131 patients were included in this study and divided into LCL (n = 19) and OCL (n = 112) groups. LCLs were matched to OCLs (1:2) using a propensity score matching (PSM) based on nine preoperative variables, including patient demographics and tumor characteristics. The pathological results, perioperative and postoperative parameters, and short-term outcomes were compared between the two groups. RESULTS: After PSM, there were 18 and 36 patients in the LCL and OCL groups, respectively. Baseline characteristics were comparable after matching. LCL was associated with less blood (100 vs. 300 ml, respectively; P < 0.001) and a shorter postoperative stay (6.0 vs 8.0 days, respectively; P = 0.003). Most patients' resection margins were > 10 mm in the LCL group (P = 0.021), and all patients with malignancy in both groups achieved R0 resection. In terms of early postoperative outcomes, the overall morbidity rate was identical in each group (11.1% vs. 11.1%, respectively; P = 1.000). No mortality occurred in either group. CONCLUSIONS: Laparoscopy is a feasible choice for resection of tumors located in the caudate lobe with acceptable perioperative results.

Cyanidin-3-O-Glucoside Supplementation Ameliorates Metabolic Insulin Resistance via Restoration of Nitric Oxide-Mediated Endothelial Insulin Transport.

SCOPE: Anthocyanin cyanidin-3-O-glucoside (Cy3G) possesses a great potential in prevention of diabetes and its vascular complications while the underlying mechanisms are still far from clear. Accumulating evidence suggests that endothelial insulin transport plays a critical role in regulating metabolic insulin sensitivity. Whether Cy3G can modulate metabolic insulin resistance via regulating endothelial insulin transport is not reported yet. METHODS AND RESULTS: Palmitic acid (PA)-treated mouse aortic endothelial cells (MAECs) model and high-fat diet (HFD) fed mice model are used. Compared with HFD mice, Cy3G supplementation decrease exogenous insulin content in skeletal muscle and ameliorate metabolic insulin resistance. In culture, Cy3G can directly ameliorate PA-induced impairment on FITC-insulin uptake in MAECs. Mechanistically, Cy3G can effectively decrease inflammatory cytokines and toll-like receptor 4 (TLR4)/nuclear factor-kappa-B inhibitor alpha (IκBα) activation, and restore the attenuated Akt/eNOS signaling pathway. Blunted nitric oxide (NO) synthase with N-nitro-l-arginine methyl ester (L-NAME) can effectively abolish the protective role of Cy3G on endothelial insulin transport and insulin-stimulated glucose utilization in HFD-fed mice. CONCLUSIONS: These findings suggest that Cy3G supplementation can directly restore the attenuated nitic oxide-mediated endothelial insulin transport and thereby ameliorate metabolic insulin resistance. Our finding can provide a novel explanation for the anti-diabetic effects of Cy3G.

LncSHRG promotes hepatocellular carcinoma progression by activating HES6.

Hepatocellular carcinoma, one of the most common cancers, leads to mass mortality worldwide currently. However, the underlying mechanism of its oncogenesis remains to be elucidated. Here we identified that a long noncoding RNA, lncSHRG, was greatly upregulated in human hepatocellular carcinoma samples. We found that lncSHRG was essential for liver cancer cell proliferation and tumor propagation in mice. In mechanism, lncSHRG recruits SATB1 to bind to HES6 promoter and initiates HES6 expression. HES6, which is highly expressed in hepatocellular carcinoma, promotes tumor cell proliferation. High expression level of HES6 is positively correlated with clinical severity and poor prognosis of people with hepatocellular carcinoma. Altogether, our research provides a new insight on the mechanism of hepatocellular carcinoma progression.