LECT2, a Ligand for Tie1, Plays a Crucial Role in Liver Fibrogenesis.

Liver fibrosis is a very common condition seen in millions of patients with various liver diseases, and yet no effective treatments are available owing to poorly characterized molecular pathogenesis. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2) is a functional ligand of Tie1, a poorly characterized endothelial cell (EC)-specific orphan receptor. Upon binding to Tie1, LECT2 interrupts Tie1/Tie2 heterodimerization, facilitates Tie2/Tie2 homodimerization, activates PPAR signaling, and inhibits the migration and tube formations of EC. In vivo studies showed that LECT2 overexpression inhibits portal angiogenesis, promotes sinusoid capillarization, and worsens fibrosis, whereas these changes were reversed in Lect2-KO mice. Adeno-associated viral vector serotype 9 (AAV9)-LECT2 small hairpin RNA (shRNA) treatment significantly attenuates fibrosis. Upregulation of LECT2 is associated with advanced human liver fibrosis staging. We concluded that targeting LECT2/Tie1 signaling may represent a potential therapeutic target for liver fibrosis, and serum LECT2 level may be a potential biomarker for the screening and diagnosis of liver fibrosis.

MACC1 and Gasdermin-E (GSDME) regulate the resistance of colorectal cancer cells to irinotecan.

Metastasis-associated in colon cancer 1 (MACC1) is an oncogene associated with the progression and metastasis of many solid cancer entities. High expression of MACC1 is found in colorectal cancer (CRC) tissues. So far, the role of MACC1 in CRC cell pyroptosis and resistance to irinotecan is unclear. The cleavage of Gasdermin-E (GSDME) is the main executors of activated pyroptosis. We found that GSDME enhanced CRC cell pyroptosis and reduced their resistance to irinotecan, while MACC1 inhibited the cleavage of GSDME and CRC cell pyroptosis, promoted CRC cell proliferation, and enhanced the resistance of CRC cells to irinotecan. Therefore, CRC cells with high MACC1 expression and low GSDME expression had higher resistance to irinotecan, while CRC cells with low MACC1 expression and high GSDME expression had lower resistance to irinotecan. Consistently, by analyzing CRC patients who received FOLFIRI (Fluorouracil + Irinotecan + Leucovorin) in combination with chemotherapy in the GEO database, we found that CRC patients with low MACC1 expression and high GSDME expression had higher survival rate. Our study suggests that the expression of MACC1 and GSDME can be used as detection markers to divide CRC patients into irinotecan resistant and sensitive groups, helping to determine the treatment strategy of patients.

P21-activated kinase 5 plays essential roles in the proliferation and tumorigenicity of human hepatocellular carcinoma.

AIM: To investigate the roles of P21-activated kinase 5 (PAK5) in proliferation and tumorigenicity of human hepatocellular carcinoma (HCC). METHODS: HCC and matched paraneoplastictis tissue samples were obtained from 30 patients. Human HCC cell lines SMMC7721, HepG2, Hep3B, SK-HEP-1, Huh-7, and liver cell line HL-7702 were examined. The expression of PAK5 gene was studied using real-time qPCR and Western blotting. Cell proliferation was quantified with the MTT assay. Cell cycle was analyzed with flow cytometry. The tumorigenicity of Lv-shRNA-transfected HepG2 cells was evaluated in BALB/cA nude mice. RESULTS: The mRNA level of PAK5 was significantly higher in 25 out of 30 HCC samples compared to the matched paraneoplastic tissues. The HCC cell lines showed varying expression of PAK5 protein, and the highest level was found in the HepG2 cells. PAK5 gene silencing in HepG2 cells markedly reduced the cell proliferation and colony formation, and induced cell cycle arrest in the G1 phase. Furthermore, PAK5 gene silencing suppressed the tumor formation in nude mice, and significantly decreased the expression of HCC-related genes Cyclin D1 and beta-catenin. CONCLUSION: PAK5 may play essential roles in the initiation and progression of human HCC. Thus, it may be an effective therapeutic target or perhaps serve as a clinical diagnostic or prognostic marker in human HCC.

[Application of anterior-inferior approach through retrohepatic tunnel for dissecting short hepatic veins in laparoscopic right hemihepatectomy].

OBJECTIVE: To explore the safety and feasibility of laparoscopic right hemihepatectomy via an anterior-inferior approach through retrohepatic tunnel in the dissection of short hepatic veins (SHVs). METHODS: After partial freeing of right liver, anterior peritoneum of inferior cava vena (ICV) was opened. Retrohepatic space was dissected via an anterior-inferior approach to establish the posterior tunnel partially. Then the first branch of right side SHVs could be freed and ligated after its exposure through the right part of retrohepatic tunnel. The above procedure was repeated until the right side SHVs or the third hepatic portal became partially or completely blocked. If right side SHVs were completely freed and ligament of right liver fully isolated, right hepatic vein could be exposed and ligated and selective blockage of the second hepatic portal blood flow accomplished. This technique was applied in 7 cases of laparoscopic right hemihepatectomy through curettage transaction and aspiration with laparoscopic Peng's multifunctional operative dissector (LPMOD). RESULTS: Six patients were treated successfully. In one case of right hepatic hemangioma, small margin auxiliary hematischesis was attempted because of troublesome hemostasis of middle hepatic vein branch. All of them underwent partial dissection of right side of SHVs. Two cases had complete dissection in which right hepatic vein was freed and ligated, the second hepatic porta blood flow controlled and right hemihepatectomy anatomically achieved. Operative duration was 300-540 min [mean, 399.1 ± 74.7]. The time of dissecting hepatic porta was 30-75 min [mean, 50.7 ± 16.2]. The time of dissecting SHVs was 35-95 min [mean, 57.1 ± 22.1]. The time of liver transection was 60-160 min [mean, 115.9 ± 32.3]. Operative blood loss had a volume at 600-3000 ml [mean, 1485.7 ± 809.2]. The postoperative hospital stay was 10-18 days [mean, 12.4 ± 2.6]. The postoperative time for ambulation, diet and flatus was 2-4, 1-4 and 2-4 days respectively. No severe postoperative complications occurred. CONCLUSION: During laparoscopic right hemihepatectomy, dissecting SHVs is both safe and feasible through a retrohepatic tunnel via an anterior-inferior approach.

Lesion human leukocyte antigen-E is associated with favourable prognosis for patients with oesophageal squamous cell carcinoma.

OBJECTIVE: To investigate the clinical significance of human leukocyte antigen (HLA)-E levels in oesophageal squamous cell carcinoma (ESCC). METHODS: The levels of HLA-E immunostaining in ESCC lesions and 47 corresponding adjacent normal tissues were measured using immunohistochemistry. The correlation between the levels of immunostaining and clinical parameters was analysed. RESULTS: This study analysed 110 paraffin-embedded primary tumour lesions and 47 case-controlled paracancerous tissues that were surgically resected from 110 patients with ESCC. Positive immunostaining for HLA-E was observed in 88.2% (97 of 110) of ESCC lesions and 29.8% (14 of 47) of normal oesophageal tissues. There was no correlation between HLA-E immunostaining in ESCC lesions and clinicopathological characteristics such as lymph node metastasis, tumour-node-metastasis stage and differentiation grade. Kaplan-Meier survival analysis revealed a significantly better prognosis in patients with higher levels of HLA-E immunostaining than in those with lower levels of HLA-E immunostaining; overall survival was 28.6 months (95% confidence interval [CI], 23.2, 34.0) versus 15.3 months (95% CI, 11.5, 19.1), respectively. Furthermore, multivariate analysis showed that the HLA-E level was an independent prognostic factor in patients with ESCC. CONCLUSION: A higher level of HLA-E immunostaining was associated with favourable survival in patients with ESCC.

HGF/R-spondin1 rescues liver dysfunction through the induction of Lgr5+ liver stem cells.

Induction of endogenous adult stem cells by administering soluble molecules provides an advantageous approach for tissue damage repair, which could be a clinically applicable and cost-effective alternative to transplantation of embryonic or pluripotent stem cell-derived tissues for the treatment of acute organ failures. Here, we show that HGF/Rspo1 induce liver stem cells and rescue liver dysfunction. Carbon tetrachloride treatment promotes both fibrosis and Lgr5+ liver stem cell proliferation, whereas Lgr5 knockdown worsens fibrosis. Injection of HGF in combination with Rspo1 increases the number of Lgr5+ liver stem cells and improves liver function by attenuating fibrosis. We observe Lgr5+ liver stem cells in human liver fibrosis tissues, and once they are isolated, these cells are able to form organoids, and treatment with HGF/Rspo1 promotes their expansion. We suggest that Lgr5+ liver stem cells represent a valuable target for liver damage treatment, and that HGF/Rspo1 can be used to promote liver stem cell expansion.

Rpb3 promotes hepatocellular carcinoma through its N-terminus.

The expression of RNA polymerase II subunit 3 (Rpb3) was found frequent up-regulation in Hepatocellular carcinoma (HCC) tumors. Significant associations could also be drawn between increased expressions of Rpb3 and advance HCC staging and shorter disease-free survival of patients. Overexpression of Rpb3 increased HCC cell proliferation, migratory rate and tumor growth in nude mice, whereas suppression of Rpb3 using shRNA inhibited these effects. For mechanism study, we found that Rpb3 bound directly to Snail, downregulated E-cadherin, induced HCC cells epithelial-mesenchymal transition (EMT). In particular, N-terminus of Rpb3 blocked Rpb3 binding to Snail, inhibited Rpb3-high-expression HCC cells proliferation, migration, tumor growth in nude mice, and also inhibited DEN-induced liver tumorigenesis. Furthermore, N-terminus of Rpb3 did not inhibit normal liver cells or Rpb3-low-expression HCC cells proliferation. These findings suggest that N-terminus of Rpb3 selectively inhibits Rpb3-high-expression HCC cells proliferation. N-terminus of Rpb3 may be useful in treating patients diagnosed with Rpb3-high-expression HCC.