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Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Although it has been known that hepatic stellate cells (HSCs) play critical roles in the development and progression of HCC, the molecular mechanism underlying crosstalk between HSCs and cancer cells still remains unclear. Here, we investigated the interactions between HSCs and cancer cells through an indirect co-culture system. The expressions of cellular and exosomal miR-148a-3p were evaluated by quantitative real-time PCR. Cell counting kit-8 was used for evaluating cell growth

Monocarboxylate transporter (MCT) 4 is a high-affinity lactate transporter that is primarily involved in the maintenance of intracellular pH homeostasis and highly expressed in different tumors. However, the role of MCT4 in modulating immune responses against HCC remains unknown.In this study, we demonstrated that MCT4 was overexpressed in HCC, which was associated with poor prognosis in patients. Genetic or pharmacological inhibition of MCT4 using VB124 (a highly potent MCT4 inhibitor) suppressed HCC tumor growth in immunocompetent mice model by enhancing CD8Our results revealed that lactate exportation by MCT4 has a tumor-intrinsic function in generating an immunosuppressive HCC environment and demonstrated the proof of the concept of targeting MCT4 in tailoring HCC immunotherapeutic approaches.

The associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) for hepatocellular carcinoma (HCC) with fibrosis/cirrhosis is often associated with limited growth of future liver remnant (FLR). We introduced a new procedure named transcatheter arterial embolization-salvaged ALPPS (TAE-salvaged ALPPS) which was shown to be especially suitable for HCC patients with cirrhosis or fibrosis who failed adequately to respond to conventional ALPPS. The short-term efficacy and safety for the TAE-salvaged ALPPS on patients with HCC and fibrosis/cirrhosis were studied.Consecutive HCC patients who underwent TAE-salvaged ALPPS in our hospital between November 2016 and June 2020 were retrospectively studied. The new ALPPS procedure included conventional ALPPS stage-1 using associating liver partition and portal vein ligation. When FLR failed to reach sufficient hypertrophy, TAE was carried out 2 weeks later followed by liver resection 3 weeks after ALPPS stage-1.Nine of 10 patients had a single tumor (median diameter 14.0 cm, range, 5.2-17 cm). The remaining patient had multiple tumors (diameter of one tumor 14.0 cm, and two satellite foci 2.0 and 3.0 cm). R0 resection was achieved in all patients (100%) after a median of 21 days. Six patients had cirrhosis, 1 had METAVIR grade-3 fibrosis, and 3 had METAVIR grade-2 fibrosis. The median increase in FLR volume after TAE-salvaged ALPPS was 69.7% (34.4-143.9%). The absolute and relative kinetic growth rates (KGRs) were 9.9 (7.1-17.3) mL/day and 3.4% (1.9-7.2%)/day, respectively. The median absolute KGRs were 15.7, 2.6, and 19.5 mL/day in the first, second, and third postoperative weeks after ALPPS stage-1, respectively. The rapid increase in KGR on the third week was induced by TAE. The overall postoperative morbidity rates were 50,0% (5/10), 20.0% (2/10) and 70.0% (7/10) after ALPPS stage-1, TAE and ALPPS stage-2, respectively. The 90-day mortality rate was 10.0% (1/10). The median overall survival was 40 months.The new TAE-salvaged ALPPS induced significant increases in FLR volumes within 3 weeks in patients with HCC and fibrosis/cirrhosis. The procedure is promising in treating patients with HCC and fibrosis/cirrhosis who fail to achieve sufficient FLR hypertrophy after conventional ALPPS stage-1.

Background Genetic alterations play an important role in the progression of colorectal cancer (CRC). Identifying new biomarkers to assess the prognosis of patients with CRC is critical. Cartilage intermediate layer protein 2 (CILP2) gene, screened from TCGA database by bioinformatics, may be closely related to the progression of CRC. CILP2 was barely reported with clinical features of tumors. Materials and methods Clinical information and RNA-seq data were derived from TCGA colorectal carcinoma cohort. CILP2 expression at mRNA level was estimated by bioinformatical analysis of TCGA cases. Tissue microarray (TMA) was constructed containing paraffin-embedded 64 pairs of CRC and matched adjacent normal tissues. The expression at the protein level was detected in 64 pairs of CRC and matched adjacent normal tissues by immunohistochemical analysis. CILP2 expression level and its clinical value were estimated by bioinformatical analysis with linear and logistic regression. Survival analysis was performed between high and low groups of CILP2 expression by Cox regression analysis, and the P value was calculated by the log-rank test. The Kaplan-Meier curves were tested by the log-rank test. Results CILP2 was statistically significantly higher expressed in the CRC tissues when compared with paired adjacent normal tissues in TCGA cohort (P < 0.001) and in the TMA cohort (P = 0.001). Also, CILP2 high expression was strongly correlated with T3/4 stage (P = 0.001), N1/2/3 stage (P = 0.005), M1 stage (P = 0.048), and higher clinical stage (UICC 2010 stage) (P < 0.001) in TCGA cohort, and also positively associated with T3/4 stage (P = 0.022) and higher clinical stage (UICC 2010 stage) (P = 0.03) in TMA cohort. Furthermore, CILP2 overexpression predicted poor prognosis and could be an independent prognostic factor (P = 0.003). Conclusion We revealed that CILP2 is associated with advanced stages and could play a role as an independent predictor of poor survival in CRC.

Background: Genetic alterations play an important role in the progression of colorectal cancer. Identifying new biomarkers to assess the prognosis of patients with colorectal cancer is critical. Cartilage Intermediate Layer Protein 2 (CILP2) gene, screened from the TCGA database by bioinformatics, may be closely related to the progression of colorectal cancer. CILP2 was barely reported with clinical features of tumors.Materials and methods: Clinical information and RNA-seq data were derived from the TCGA colorectal carcinoma cohort. CILP2 expression at mRNA level was estimated by bioinformatical analysis of TCGA cases. Tissue microarray (TMA) was constructed containing paraffin-embedded 64 pairs of colorectal cancer and matched adjacent normal tissues. The expression at the protein level was detected in 64 pairs of colorectal cancer and matched adjacent normal tissues by immunohistochemical analysis. CILP2 expression level and its clinical value were estimated by bioinformatical analysis with linear and logistic regression. Survival analysis was performed between high and low groups of CILP2 expression by Cox regression analysis, and the P-value was calculated by the log-rank test. Kaplan-Meier curves were tested by the log-rank test.Results: CILP2 was statistically significantly higher expressed in the colorectal cancer tissues when compared with paired adjacent normal tissues in the TCGA cohort (PP=0.001). Also, CILP2 high-expression was strongly correlated with T3/4 stage (P=0.001), N1/2/3 stage (P=0.005), M1 stage (P=0.048), and higher clinical stage (UICC 2010 stage) (PP=0.022) and higher clinical stage (UICC 2010 stage) (P=0.03) in TMA cohort. Furthermore, CILP2 overexpression predicted poor prognosis and could be as an independent prognostic factor (P=0.003).Conclusion: We revealed that CILP2 is associated with advanced stages and could play a role as an independent predictor of poor survival in colorectal cancer.

Background: In previous studies, we provided evidence suggesting the involvement of γ-synuclein in growth, invasion, and metastasis of colon cancer cells in vitro and in vivo. Among γ-synuclein downstream genes, the microtubule-associated protein 1 Light Chain 3 (LC3), an autophagy gene, was screened by gene expression profile chip analysis. Objective: We planned to investigate the functional effects of γ-synuclein on autophagy induced by ER stress in colon cancer cells. Methods: We investigated the functional effects of γ-synuclein on autophagy and apoptosis induced by Thapsigargin (TG), ER stress-inducing agent, in colon cancer cell lines using immunofluorescence staining, RT-PCR, western blot, CCK8 test, flow cytometry analysis, and transmission electron microscopy. To further determine how γ-synuclein regulated autophagy and apoptosis, PD98059 (ERK inhibitor), SP600125 (ERK inhibitor), anisomycin (JNK activator), and c-Jun siRNA were used respectively in γ-synuclein siRNA transfected HCT116 cells. Then, autophagy proteins, apoptosis proteins, and pathway proteins were detected by western blot analysis. The expression of autophagy genes was assessed by RT-PCR. Results: Our data showed that ER stress-induced colon cancer cells autophagy mainly in the early stage (0-24h) and apoptosis mainly in the late stage (24-48h). ER stress up-regulated γ-synuclein gene and protein expression in colon cancer cells, accompanied by autophagy. γ-synuclein protected HCT116 cells by enhancing autophagy in the early stage (0-24h) through activation of ERK and JNK pathway and inhibiting apoptosis in the late stage (24-48h) through inhibition of the JNK pathway. γ-synuclein could promote autophagy via the JNK pathway activation of ATG genes, LC3, Beclin 1, and ATG7. γ-synuclein may play a role in the transition between autophagy and apoptosis in our model. Conclusion: Overall, we provided the first experimental evidence to show that γ-synuclein may play an important role in autophagy that protects colon cancer cells from ER stress. Therefore, our data suggest a new molecular mechanism for γ-synuclein-mediated CRC progression.

Background: Genetic alterations play an important role in the progression of colorectal cancer (CRC). Identifying new biomarkers to assess the prognosis of patients with colorectal cancer is critical. Cartilage Intermediate Layer Protein 2 (CILP2) gene, screened from the TCGA database by bioinformatics, may be closely related to the progression of colorectal cancer. CILP2 was barely reported with clinical features of tumors.Materials and methods: Clinical information and RNA-seq data were derived from the TCGA colorectal carcinoma cohort. CILP2 expression at mRNA level was estimated by bioinformatical analysis of TCGA cases. Tissue microarray (TMA) was constructed containing paraffin-embedded 64 pairs of CRC and matched adjacent normal tissues. The expression at the protein level was detected in 64 pairs of CRC and matched adjacent normal tissues by immunohistochemical analysis. CILP2 expression level and its clinical value were estimated by bioinformatical analysis with linear and logistic regression. Survival analysis was performed between high and low groups of CILP2 expression by Cox regression analysis, and the P-value was calculated by the log-rank test. Kaplan-Meier curves were tested by the log-rank test. Results: CILP2 was statistically significant higher expressed in the colorectal cancer tissues when compared with paired adjacent normal tissues in the TCGA cohort (PP=0.001). Also, CILP2 high-expression was strongly correlated with T3/4 stage (P=0.001), N1/2/3 stage (P=0.005), M1 stage (P=0.048), and higher clinical stage (UICC 2010 stage) (PP=0.022) and higher clinical stage (UICC 2010 stage) (P=0.03) in TMA cohort. Furthermore, CILP2 overexpression predicted poor prognosis and could be as an independent prognostic factor (P=0.003).Conclusion: We revealed that CILP2 is associated with advanced stages and could play a role as an independent predictor of poor survival in colorectal cancer.

Autophagy plays an important role in the physiology and pathology of the liver. It is involved in the development of many liver diseases such as α-1-antitrypsin deficiency, chronic hepatitis virus infection, alcoholic liver disease, nonalcoholic fatty liver disease, and liver cancer. Autophagy has thus become a new target for the treatment of liver diseases. How to treat liver diseases by regulating autophagy has been a hot topic.

Background Cartilage Intermediate Layer Protein 2 (CILP2), a glycoprotein with mutations associated with abnormal blood lipid concentrations in normal and cardiovascular diseases patients, was barely reported with clinical features of tumors. We evaluated the role of CILP2 among all stages and histology in colorectal cancer (CRC) in the Cancer Genome Altas (TCGA), and furtherly verified using immunohistochemistry assay within human CRC tissues. Materials and methods Clinical information and RNA-seq data were derived from TCGA colorectal carcinoma cohort. CILP2 expression at mRNA level was estimated by bioinformatical analysis of TCGA cases. Tissue microarray (TMA) was constructed containing paraffin-embedded 64 pairs of CRC and matched adjacent normal tissues. The expression at protein level was detected in 64 pairs of CRC and matched adjacent normal tissues by immunohistochemical analysis. CILP2 expression level and its clinical value were estimated by bioinformatical analysis with linear and logistic regression. Survival analysis was performed between high and low groups of CILP2 expression by Cox regression analysis, and P value was calculated by log-rank test. Kaplan-Meier curves were tested by log-rank test. Results CILP2 was significantly higher expressed in the colorectal cancer tissues when compared with paired adjacent normal tissues in TCGA cohort (P P = 0.001). In addition, CILP2 high-expression was strongly correlated with T3/4 stage (P = 0.001), N1/2/3 stage (P = 0.005), M1 stage (P = 0.048), and higher clinical stage (UICC 2010 stage) (P P = 0.022) and higher clinical stage (UICC 2010 stage) (P = 0.03) in TMA cohort. Furthermore, CILP2 overexpression predicted poor prognosis and could be as an independent prognostic factor (P = 0.003). Conclusion We revealed that CILP2 is associated with advanced stages and could play a role as an independent predictor of poor survival in colorectal cancer.

Intrahepatic cholangiocarcinoma (ICC) remains a highly heterogeneous disease with poor prognosis. Tumor‐infiltrating lymphocytes were predictive in various cancers, but their prognostic value in ICC is less clear. A total of 168 ICC patients who had received liver resection were enrolled and assigned to the derivation cohort. Sixteen immune markers in tumor and peritumor regions were examined by immunohistochemistry. A least absolute shrinkage and selection operator model was used to identify prognostic markers and to establish an immune signature for ICC (ISICC). An ISICC‐applied prediction model was built and validated in another independent dataset. Five immune features, including CD3peritumor (P), CD57P, CD45RAP, CD66bintratumoral (T) and PD‐L1P, were identified and integrated into an individualized ISICC for each patient. Seven prognostic predictors, including total bilirubin, tumor numbers, CEA, CA19‐9, GGT, HBsAg and ISICC, were integrated into the final model. The C‐index of the ISICC‐applied prediction model was 0.719 (95% CI, 0.660‐0.777) in the derivation cohort and 0.667 (95% CI, 0.581‐0.732) in the validation cohort. Compared with the conventional staging systems, the new model presented better homogeneity and a lower Akaike information criteria value in ICC. The ISICC‐applied prediction model may provide a better prediction performance for the overall survival of patients with resectable ICC in clinical practice., Using tissue microarray, we examined the density of 16 immune biomarkers in 280 ICC patients who underwent hepatectomy, and established a novel ISICC‐based prediction model (IPM) to predict patients’ overall survival with bilirubin, tumor numbers, CEA, CA19‐9, γ‐glutamyl transferase (GGT), HBsAg and ISICC. The new model may provide a better prediction performance for the overall survival of patients with resectable ICC in clinical practice.

Insufflation with standard cold-dry CO(2) during laparoscopic surgery has been shown to predispose patients to hypothermia and peritoneal injury. This study aimed to compare the effect of prolonged cold-dry CO(2) insufflation with heated-humidified CO(2) insufflation (3-5 h) on hypothermia, peritoneal damage, and intra-abdominal adhesion formation in a rat model.A total of 160 Wistar rats were randomized to undergo no insufflation or insufflation with cold-dry CO(2) (21 degrees C,1% relative humidity) or heated-humidified CO(2) (37 degrees C, 95% relative humidity) for 3, 4, or 5 h. Core body temperature was measured via rectum before and during insufflations. Peritoneal samples were taken at 6, 24, 48, and 96 h after treatments and analyzed with light microscopy and scanning electron microscopy. Intra-abdominal adhesions were evaluated 2 weeks later.Core body temperature significantly decreased in the cold-dry group, whereas it was maintained and increased in the heated-humidified group. Scanning electron microscopy and light microscopy studies showed intense peritoneal injury in the cold-dry CO(2) group but significantly less damages in the heated-humidified group. Increased intra-abdominal adhesion formation was observed in the cold-dry CO(2) group, while no adhesions were found in the rats insufflated with heated-humidified CO(2).Heated-humidified CO(2) insufflation results in significantly less hypothermia, less peritoneal damage, and decreased adhesion formation as compared with cold-dry CO(2) insufflation. Heated-humidified CO(2) may be more suitable for insufflation application in prolonged laparoscopic surgery.

Lysyl oxidase like 4 (LOXL4), a member of the secreted copper-dependent amine oxidases that contribute to the assemble and maintenance of the extracellular matrix (ECM), was found to be up-regulated or down-regulated in different cancer types, suggesting its paradoxical roles in cancer. The specific role of LOXL4 in hepatocellular carcinoma (HCC), however, is still yet to be defined. Twenty-eight pairs of HCC specimens were used for LOXL4 mRNA expression analysis. The mRNA expression in HCC cell lines was examined, and HepG2 was selected for LOXL4 small interfering RNA (siRNA) interference to investigate the biological function of LOXL4, LOXL4 immunohistochemical staining was performed using a tissue microarray containing 298 HCC patients. The prognostic and diagnostic value of LOXL4 was evaluated using Cox regression and Kaplan-Meier analysis. LOXL4 mRNA or protein expression was significantly lower in HCC tissues than peritumoral tissues (LOXL4 mRNA expression, P = 0.018; LOXL4 protein expression, P < 0.001). Low LOXL4 expression was associated with lower overall survival (OS) rates and higher cumulative recurrence rates. Multivariate analysis indicated that LOXL4 was an independent prognostic indicator for OS and time to recurrence (TTR). Our results revealed that LOXL4 was down-regulated in HCC and correlated with aggressive tumors and a worse clinical outcome. LOXL4 may be a potential biomarker to identify the HCC patients with a higher risk of recurrence.