GPR37 promotes colorectal cancer liver metastases by enhancing the glycolysis and histone lactylation via Hippo pathway.

Liver metastases are commonly detected in a range of malignancies including colorectal cancer (CRC), unfortunately no effectively strategies for CRC liver metastasis (CRLM). In this study, we found GPR37 expression dramatically increased in human CRLM specimens and associated poor prognosis. GPR37 depletion greatly suppressed the liver metastasis in the mouse models of CRLM. Functional experiments showed that GPR37 knockdown inhibited the growth by reducing the glycolysis of CRC cells. Also, GPR37 knockdown in tumor cells produced decreased levels of two chemokines involved in neutrophil accumulation, which abrogated neutrophil recruitment in the tumor microenvironment of CRLM. Finally, the mechanism studies revealed that GPR37 could activate the hippo pathway, thereby promoting LDHA expression and glycolysis. This leads to increased lactylation of H3K18la, resulting in up-regulation of CXCL1 and CXCL5. These results support a role of the GPR37 in modulating the tumor metabolism and microenvironment in CRLM and GPR37 could be a potential therapeutic target.

TRIM14 Overexpression Induces Chemoresistance and Malignant Behaviors of Hepatocellular Carcinoma Cells by Activating the STAT3/HIF-1α Pathway.

Members of the tripartite motif (TRIM)-containing protein family have been found to be involved in the progression of hepatocellular carcinoma (HCC). TRIM14 exerts a promotive impact on several cancers. This study aimed to explore the function and mechanism of TRIM14 in HCC. TRIM14 expression in HCC tissues and HCC cell lines was detected. The overexpression or knockdown model of TRIM14 was established in HCC cell lines. Cell Counting Kit-8 (CCK-8) assay, flow cytometry, Transwell assay, RT-PCR, Western blot, and immunofluorescence were performed to verify the influence of TRIM14 on cell proliferation, sensitivity to chemotherapy drugs, apoptosis, migration, invasion, and autophagy. A xenograft tumor model was used to confirm the impact of TRIM14 on tumor cell growth. As shown by the data, TRIM14 level was notably higher in the tumor tissues of HCC patients than in the adjacent tissues. The overall survival rate of patients with a high TRIM14 expression was relatively lower than that of patients with a low TRIM14 expression. TRIM14 upregulation enhanced the proliferation, autophagy, migration, and invasion of HCC cells and chemoresistant HCC cells and decreased apoptosis. TRIM14 knockdown contributed to the opposite effects. In in vivo experiments, TRIM14 upregulation bolstered tumor growth. Western blot analysis revealed that TRIM14 upregulation boosted signal transducer and activator of transcription3 (STAT3) and hypoxia-inducible factor-1alpha (HIF-1α) expression, and TRIM14 knockdown suppressed their expression. Moreover, repressing STAT3 and HIF-1α could mitigate the tumor-promoting role of TRIM14 in HCC cells. Overall, TRIM14 facilitated malignant HCC development and induced chemoresistance in HCC cells by activating the STAT3/HIF-1α axis.

Adjuvant TACE may not improve recurrence-free or overall survival in HCC patients with low risk of recurrence after hepatectomy.

Background: To identify whether adjuvant transarterial chemoembolization (TACE) can improve prognosis in HCC patients with a low risk of recurrence (tumor size ≤ 5 cm, single nodule, no satellites, and no microvascular or macrovascular invasions) after hepatectomy. Methods: The data of 489 HCC patients with a low risk of recurrence after hepatectomy from Shanghai Cancer Center (SHCC) and Eastern Hepatobiliary Surgery Hospital (EHBH) were retrospectively reviewed. Recurrence-free survival (RFS) and overall survival (OS) were analyzed with Kaplan-Meier curves and Cox proportional hazards regression models. The effects of selection bias and confounding factors were balanced using propensity score matching (PSM). Results: In the SHCC cohort, 40 patients (19.9%, 40/201) received adjuvant TACE, and in the EHBH cohort, 113 patients (46.2%, 133/288) received adjuvant TACE. Compared to the patients without adjuvant TACE after hepatectomy, patients receiving adjuvant TACE had significantly shorter RFS (P=0.022; P=0.014) in both cohorts before PSM. However, no significant difference existed in OS (P=0.568; P=0.082). Multivariate analysis revealed that serum alkaline phosphatase and adjuvant TACE were independent prognostic factors for recurrence in both cohorts. Furthermore, significant differences existed in tumor size between the adjuvant TACE and non-adjuvant TACE groups in the SHCC cohort. There were differences in transfusion, Barcelona Clinic Liver Cancer stage and tumor-node-metastasis stage in the EHBH cohort. These factors were balanced by PSM. After PSM, patients with adjuvant TACE after hepatectomy still had significantly shorter RFS than those without (P=0.035; P=0.035) in both cohorts, but there was no difference in OS (P=0.638; P=0.159). Adjuvant TACE was the only independent prognostic factor for recurrence in multivariate analysis, with hazard ratios of 1.95 and 1.57. Conclusions: Adjuvant TACE may not improve long-term survival and might promote postoperative recurrence in HCC patients with a low risk of recurrence after hepatectomy.

ZNF655 promotes the progression of hepatocellular carcinoma through PSMB8.

Hepatocellular carcinoma (HCC) is a type of liver cancer that is associated with high mortality rates. This study aims to investigate the role of ZNF655, a member of the zinc finger protein family, in the development of HCC. Immunohistochemical staining analysis was conducted to evaluate the expression of ZNF655 in HCC patient samples. Lentivirus-mediated ZNF655 knockdown was established in HCC cell lines (BEL-7402 and HCCLM3). The effects of ZNF655 on different aspects of HCC cell behavior such as proliferation, apoptosis, cycle, migration and tumor formation were examined. Downstream targets of ZNF655 in HCC were identified and verified through loss/gain-of-function experiments. Clinically, ZNF655 expression was elevated in HCC and increased with the severity of the disease. Functionally, inhibition of ZNF655 expression reduced the progression of HCC cells by decreasing proliferation, causing apoptosis, arresting cell cycle retention in G2, suppressing migration, and attenuating tumor formation in mice. Mechanistically, the proteasome subunit beta type-8 (PSMB8) was found to be co-expressed with ZNF655 in HCC, and PSMB8 knockdown weakened the promotion of ZNF655 overexpression on HCC. In summary, these findings suggest that ZNF655 promotes the progression of HCC through PSMB8, and inhibition of its expression may be a promising therapeutic target for HCC.

Safety and efficacy of GEMOX plus donafenib and tislelizumab as first-line therapy for advanced epithelial malignant biliary tract cancer.

AIM: This study was aimed to evaluate the safety and the efficacy of gemcitabine and oxaliplatin (GEMOX) combined with donafenib plus tislelizumab as the first-line treatment for patients with unresectable biliary tract cancer (BTC). METHODS: This is a prospective single-center exploratory study. Eligible patients (Stage III/IV BTC, at least one measurable disease according to RECIST v1.1, etc.) received gemcitabine 1000 mg/m2 IV Q3W, oxaliplatin 100 mg/m2 IV Q3W, donafenib 200 mg PO BID, and tislelizumab 200 mg IV Q3W until disease progression, unacceptable toxicity, or withdrawal of consent whichever occurred first. The primary endpoint was safety and secondary endpoints included disease control rate (DCR), objective response rate (ORR), conversion rate, and overall survival (OS). RESULTS: A total of 13 patients were enrolled. The median follow-up time was 420 days (range 345-487). The median duration of treatment was four cycles (range 1-15). The incidence of ≥Grade 3 treatment-related adverse events (TRAEs) was 53.8% and no Grade 5 TRAE. The most frequent Grade 3-4 TRAEs were rash (4/13, 30.8%), platelet count decreased (2/13, 15.4%), and fatigue (2/13, 15.4%). Tumor response was assessed in eight evaluable patients; ORR was 25.0% (95% CI, 3.2%-65.1%) and DCR 87.5% (95% CI, 47.3%-99.7%). The median PFS was 4.8 months (95% CI, 1.25-NE). Three Stage III patients underwent subsequent surgery with a conversion rate of 23.1%. The median OS was not estimable. CONCLUSIONS: GEMOX combined with donafenib plus tislelizumab as the first-line therapy for unresectable BTC showed manageable toxicity and encouraging efficacy especially in terms of promising conversion rate in Stage III patients.

Value and prognostic factors of repeat hepatectomy for recurrent colorectal liver metastasis.

BACKGROUND: More than 50% of patients with colorectal cancer develop liver metastases. Hepatectomy is the preferred treatment for resectable liver metastases. This review provides a perspective on the utility and relevant prognostic factors of repeat hepatectomy in recurrent colorectal liver metastasis (CRLM). DATA SOURCES: The keywords "recurrent colorectal liver metastases", "recurrent hepatic metastases from colorectal cancer", "liver metastases of colorectal cancer", "repeat hepatectomy", "repeat hepatic resection", "second hepatic resection", and "prognostic factors" were used to retrieve articles published in the PubMed database up to August 2020. Additional articles were identified by a manual search of references from key articles. RESULTS: Despite improvements in surgical methods and perioperative chemotherapy, recurrence remains common in 37%-68% of patients. Standards or guidelines for the treatment of recurrent liver metastases are lacking. Repeat hepatectomy appears to be the best option for patients with resectable metastases. The commonly reported prognostic factors after repeat hepatectomy were R0 resection, carcinoembryonic antigen level, the presence of extrahepatic disease, a short disease-free interval between initial and repeat hepatectomy, the number (> 1) and size (≥ 5 cm) of hepatic lesions, requiring blood transfusion, and no adjuvant chemotherapy after initial hepatectomy. The median overall survival after repeat hepatectomy ranged from 19.3 to 62 months, and the 5-year overall survival ranged from 21% to 73%. Chemotherapy can act as a test for the biological behavior of tumors with the goal of avoiding unnecessary surgery, and a multimodal approach involving aggressive chemotherapy and repeat hepatectomy might be the treatment of choice for patients with early recurrent CRLM. CONCLUSIONS: Repeat hepatectomy is a relatively safe and effective treatment for resectable recurrent CRLM. The presence or absence of prognostic factors might facilitate patient selection to improve short- and long-term outcomes.

A Practical Risk Classification of Early Recurrence in Hepatocellular Carcinoma Patients with Microvascular invasion after Hepatectomy: A Decision Tree Analysis.

PURPOSE: This study was designed to establish risk classifications for early recurrence in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI) after hepatectomy. METHODS: The data of 563 HCC patients with MVI after hepatectomy from two hospitals were retrospectively reviewed. Kaplan-Meier curves and Cox proportional hazards regression models were used to analyse early recurrence. The risk classification for early recurrence was established by using classification and regression tree (CART) analysis and validated by using two independent validation cohorts from two hospitals. RESULTS: Multivariate analysis revealed that four indices, namely, infection of chronic viral hepatitis, MVI classification, tumour size, and serum alpha-fetoprotein (AFP), were independent prognostic factors for early recurrence in HCC patients with MVI. By CART analysis, MVI classification and serum AFP became the nodes of a decision tree and 3-stratification classifications that satisfactorily determined the risk of early recurrence were established. The area under the time-dependent receiver operating characteristic curve (AUC) values of the classification for early recurrence at 0.5, 1.0, and 2.0 years were 0.75, 0.73, and 0.71, respectively, which were all significantly higher than three common classic HCC stages (BCLC stage, Chinese stage, and TNM stage). The calibration curves showed good agreement between predictions by classification for early recurrence and actual survival outcomes. These prediction results also were confirmed in the independent internal and external validation cohorts. CONCLUSIONS: The 3 stratification classifications enabled satisfactory risk evaluation of early recurrence in HCC patients with MVI after hepatectomy.

LncRNA-EWSAT1 promotes hepatocellular carcinoma metastasis via activation of the Src-YAP signaling axis.

Regardless of the improvements in diagnostic and therapeutic methods, the clinical outcomes of hepatocellular carcinoma (HCC) patients remain poor. Although accumulating evidence indicates that lncRNAs (long noncoding RNAs) are essential within the control of tumorigenesis and the metastasis of cancer, the underlying mechanisms remain largely unknown. This work explored the pattern of expression and functional significance of a newly found lncRNA, Ewing sarcoma-associated transcript 1 (EWSAT1), in HCC metastasis. The results indicated that EWSAT1 was upregulated significantly in HCC relative to that in normal tissues and was correlated with an aggressive phenotype and low patient survival. Functional experiments demonstrated that EWSAT1 could promote proliferation and HCC cell metastasis both in vitro and in vivo. Mechanistically, EWSAT1 binds directly to Yes-associated protein (YAP), promotes Sarcoma gene (Src)-induced phosphorylation of YAP, facilitates nuclear translocation of YAP, and consequently, activates the transcription of Hippo-YAP signaling target genes involved in cancer evolution. This study found that EWSAT1 plays a crucial role in HCC metastasis and that it has the potential to be a prognosis biomarker and a target for therapeutics.

A population-based predictive model identifying optimal candidates for primary and metastasis resection in patients with colorectal cancer with liver metastatic.

Background: The survival benefit of primary and metastatic resection for patients with colorectal cancer with liver metastasis (CRLM) has been observed, but methods for discriminating which individuals would benefit from surgery have been poorly defined. Herein, a predictive model was developed to stratify patients into sub-population based on their response to surgery. Methods: We assessed the survival benefits for adults diagnosed with colorectal liver metastasis by comparing patients with curative surgery vs. those without surgery. CRLM patients enrolled in the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015 were identified for model construction. Other data including CRLM patients from our center were obtained for external validation. Calibration plots, the area under the curve (AUC), and decision curve analysis (DCA) were used to evaluate the performance of the nomogram compared with the tumor-node-metastasis (TNM) classification. The Kaplan-Meier analysis was performed to examine whether this model would distinguish patients who could benefit from surgery. Results: A total of 1,220 eligible patients were identified, and 881 (72.2%) underwent colorectal and liver resection. Cancer-specific survival (CSS) for the surgery group was significantly better than that for the no-surgery group (41 vs. 14 months, p < 0.001). Five factors were found associated with CSS and adopted to build the nomograms, i.e., age, T stage, N stage, neoadjuvant chemotherapy, and primary tumor position. The AUC of the CRLM nomogram showed a better performance in identifying patients who could obtain benefits in the surgical treatment, compared with TNM classification (training set, 0.826 [95% CI, 0.786-0.866] vs. 0.649 [95% CI, 0.598-0.701]; internal validation set, 0.820 [95% CI, 0.741-0.899] vs. 0.635 [95% CI, 0.539-0.731]; external validation set, 0.763 [95% CI, 0.691-0.836] vs. 0.626 [95% CI, 0.542-0.710]). The calibration curves revealed excellent agreement between the predicted and actual survival outcomes. The DCA showed that the nomogram exhibited more clinical benefits than the TNM staging system. The beneficial and surgery group survived longer significantly than the non-beneficial and surgery group (HR = 0.21, 95% CI, 0.17-0.27, p < 0.001), but no difference was observed between the non-beneficial and surgery and non-surgery groups (HR = 0.89, 95% CI, 0.71-1.13, p = 0.344). Conclusions: An accurate and easy-to-use CRLM nomogram has been developed and can be applied to identify optimal candidates for the resection of primary and metastatic lesions among CRLM patients.

Association of Simultaneous vs Delayed Resection of Liver Metastasis With Complications and Survival Among Adults With Colorectal Cancer.

Importance: Simultaneous or delayed resection of synchronous liver metastasis (SLM) with primary colorectal cancer (CRC) remains a controversial topic. Objective: To investigate the outcomes of simultaneous vs delayed resection in patients with resectable SLM. Design, Setting, and Participants: This comparative effectiveness research study included 1569 patients with resectable SLM who underwent curative-intent liver resection at 3 independent centers in China between January 1, 2000, to December 31, 2019. A 1:1 propensity score matching was performed. Follow-up was completed on August 31, 2021, and the data were analyzed from April 1 to 30, 2022. Main Outcomes and Measures: Primary outcome was the percentage of patients with at least 1 major complication within 60 days after surgery. Secondary outcomes were intraoperative and postoperative complications, overall survival (OS), and cancer-specific survival (CSS) rates. Results: Among the 1569 patients included, 1057 (67.4%) underwent delayed resection (719 men [68.0%] with a mean [SD] age of 57.4 [11.2] years), and 512 patients (310 men [60.5%] with a mean [SD] age of 57.1 [10.5] years) underwent simultaneous resection. Matching yielded 495 pairs of patients underwent simultaneous resection. The percentage of major perioperative complications did not differ between the simultaneous and delayed resection groups (34.1% vs 30.0%; P = .89). The OS rates were 65.2% at 3 years, 47.1% at 5 years, and 38.0% at 8 years for the delayed resection group and 78.0% at 3 years, 65.4% at 5 years, and 63.1% at 8 years for the simultaneous resection group (hazard ratio [HR], 1.42; 95% CI, 1.10-1.85, P = .003). The CSS rates were 68.3% at 3 years, 48.5% at 5 years, and 37.1% at 8 years for the delayed resection group and 79.2% at 3 years, 67.2% at 5 years, and 65.9% at 8 years for the simultaneous resection group (HR, 1.45; 95% CI, 1.14-1.98; P = .004). On subgroup analysis comparing the 2 strategies according to the KRAS sequence variation status, the OS rates (HR, 1.61; 95% CI, 1.45-2.18; P < .001) and CSS rates (HR, 1.62; 95 CI, 1.40-1.87; P = .003]) in the simultaneous resection group were significantly better than those in the delayed resection group in patients with KRAS wild-type tumors. Conclusions and Relevance: Results of this study suggest that complication rates did not differ when CRC and SLM were resected simultaneously and that the survival benefits of simultaneous resection were restricted to patients with KRAS wild-type tumors. Integrating molecular features into the treatment decision is a basis for accurate, individualized treatments.

The Value of Laparoscopic Simultaneous Colorectal and Hepatic Resection for Synchronous Colorectal Cancer Liver Metastasis: A Propensity Score Matching Study.

Purpose: The aim of this study is to investigate the value of total laparoscopic simultaneous colorectal and hepatic resection in patients with synchronous colorectal cancer liver metastases (sCRLMs). Methods: sCRLM patients who underwent simultaneous resection from December 2014 to December 2018 in Shanghai Cancer Center, Fudan University were recruited and analyzed retrospectively. The patients were divided into laparoscopic, open, and hybrid surgery groups. The intraoperative information, postoperative short-term outcome, and long-term survival were compared among the three groups. Propensity score matching (PSM) was performed to balance baselines. Results: A total of 281 patients were recruited. After PSM, 34 patients were selected from both the laparoscopic and the open surgery group. Forty-seven patients were also selected from both the laparoscopic and the hybrid surgery group. The clinicopathologic baselines between the laparoscopic surgery group and the other two groups were well matched. All the operation-related indicators between laparoscopic surgery and hybrid surgery were similar. However, compared with open surgery, laparoscopic surgery showed significantly longer operation time (229.09 ± 10.94 min vs. 192.24 ± 9.49 min, p = 0.013) and less intraoperative blood loss [100.00 (50.00-300.00) ml vs. 200.00 (150.00-400.00) ml, p = 0.021]. For postoperative morbidity, there was no significant difference between the laparoscopic surgery group and the hybrid or the open surgery group (23.40% vs. 31.91% and 17.65% vs. 26.47%, p = 0.356 and p = 0.380). Long-term survival analysis showed that there were no significant differences in all 1-, 3-, and 5-year overall survival, liver recurrence-free survival (RFS), and whole RFS between laparoscopic surgery and hybrid surgery (p = 0.334, p = 0.286, and p = 0.558) or open surgery (p = 0.230, p = 0.348, and p = 0.450). Conclusions: Laparoscopic simultaneous resection for sCRLM shows slight advantages in surgical safety and short-term outcome, and does not compromise long-term survival.

Hepatic resection prolongs overall survival in the selected patients with nasopharyngeal carcinoma liver metastases.

BACKGROUND: The role of surgery in nasopharyngeal carcinoma liver metastases (NCLM) remains elusive, and the current application is limited. We aim to investigate whether hepatic resection (HR) of NCLM improves survival compared with non-hepatic resection (NHR) treatment. METHODS: One hundred and thirty-three patients with NCLM from 2007 to 2017 were divided into two groups. Propensity score matching (PSM) analysis was used to compare the clinical outcomes. RESULTS: After PSM the median overall survival (OS) and the 1, 3 and 5-year OS rates in HR group were 32.60 months, 86.2%, 37.3% and 37.3%, respectively; while for NHR group these values were 19.57 months, 61.5%, 12.9% and 2.9%, respectively (P = 0.008). Multivariate analysis indicated hepatitis B virus infection (P = 0.029) and hepatic resection (P = 0.018) were independent prognostic factors. CONCLUSION: Our study revealed that hepatectomy yields a survival benefit safely compared with systemic treatments, especially for patients with the size of largest metastasis < 5 cm, unilobar distribution of liver tumor and received unanatomical hepatectomy.

Enhanced Recovery After Surgery in the Patients With Hepatocellular Carcinoma Undergoing Hemihepatectomy.

BACKGROUND: This study aims to compare the effectiveness and safety of enhanced recovery after surgery (ERAS) in patients with hepatocellular carcinoma (HCC) undergoing hemihepatectomy. METHODS: From January 2017 to June 2019, 54 and 56 patients were enrolled into the control and ERAS group, retrospectively. All the indicators related to operation, liver functions, and postoperative outcomes were included in the analysis. Propensity score matching (PSM) analysis identified 72 patients for further analysis. RESULTS: The clinicopathological characteristics were well-matched after PSM, and there were no significant differences in the operative duration, blood loss, blood transfusion, hospital costs, and most postoperative indicators in these 2 groups. In the ERAS group, D-dimer and fibrin degradation product values were significantly reduced (3.57 (2.874.60) µg/ml vs 4.81 (3.948.29) µg/ml and 11.90 (10.0418.02) µg/ml vs 15.80 (11.5529.24) µg/ml; P = .002 and P = .023, respectively). The days that semiliquid diet was allowed after surgery (2.00 (2.003.00) days vs 5.00 (4.006.00) days, P < .001), abdominal drainage tube indwelling duration (5.00 (4.005.00) days vs 5.00 (4.756.25) days, P = .004), and hospital stay after surgery (6.00 (6.007.00) days vs 8.00 (7.0010.00) days, P < .001) were also significantly shorter. The proportion of patients requiring analgesic treatment was significantly lower in the postoperative day 2 and day 4 (P < .001 and P = .025, respectively). The morbidity was significantly less (36.11% vs 69.44%, P = .005). CONCLUSIONS: ERAS programs are feasible and safe in HCC patients undergoing hemihepatectomy. Postoperative anticoagulant therapy may be one of the necessary steps.

Enhanced Recovery After Surgery in Patients With Hepatocellular Carcinoma Undergoing Laparoscopic Hepatectomy.

Objective: To compare the effectiveness and safety of enhanced recovery after surgery (ERAS) in patients with hepatocellular carcinoma (HCC) undergoing laparoscopic hepatectomy. Methods: From September 2016 to June 2019, 282 patients were enrolled, and ERAS was implemented since March 2018. All indicators related to surgery, liver function, and postoperative outcomes were included in the analysis. Propensity score matching (PSM) identified 174 patients for further comparison. Results: After PSM, the clinicopathological baselines were well-matched. The group showed significantly less intraoperative blood loss (100.00 [100.00-200.00] vs. 200.00 [100.00-300.00] ml, P = 0.001), fewer days before abdominal drainage tube removal (4.00 [3.00-4.00] days vs. 4.00 [3.00-5.00] days, P = 0.023), shorter hospital stay after surgery (6.00 [5.00-6.00] days vs. 6.00 [6.00-7.00] days, P < 0.001), and reduced postoperative morbidity (18.39 vs. 34.48%, P = 0.026). The proportion of patients with a pain score ≥ 4 was significantly lower in the ERAS group within the first 2 days after surgery (1.15 vs. 13.79% and 8.05 vs. 26.44%, P = 0.002 and P = 0.001, respectively). Pringle maneuver was performed more frequently in the ERAS group (70.11 vs. 18.39%, P < 0.001), and a significantly higher postoperative alanine aminotransferase level was also observed (183.40 [122.85-253.70] vs. 136.20 [82.93-263.40] U/l, P = 0.026). The 2-year recurrence-free survival was similar between the two groups (72 vs. 71%, P = 0.946). Conclusions: ERAS programs are feasible and safe and do not influence mid-term recurrence in HCC patients undergoing laparoscopic hepatectomy.

RNA sequencing analysis reveals the competing endogenous RNAs interplay in resected hepatocellular carcinoma patients who received interferon-alpha therapy.

BACKGROUND: Interferon-alpha (IFN-α) is a general therapeutic regimen to be utilized in hepatocellular carcinoma (HCC). However, regulatory mechanisms of IFN-α on competing endogenous RNAs (ceRNAs) level in anti-HCC relapse are rarely understood. METHODS: HCC patients with and without IFN-α treatment were calculated to analyze the expression profile of mRNA, long non-coding RNA (lncRNA), microRNA (miRNA), and circular RNA (circRNA) by RNA sequence, and significant differential expression (DE) of these types of RNAs were selected for further analysis. A ceRNA regulatory network was constructed to explore the potential mechanisms of IFN-α intervention on anti-HCC relapse. Finally, the potential prognostic associated genes among these DE RNAs were identified. RESULTS: Totally, 556 mRNAs, 120 circRNAs, 87 lncRNAs, and 96 miRNAs were differentially expressed in patients who received IFN-α treatment. A ceRNA regulatory network including a circRNA-miRNA-mRNA network which composed of 4 up- and 10 down-regulated circRNAs, 8 up- and 5 down-regulated miRNAs, 28 up- and 9 down-regulated mRNAs, and a lncRNA-miRNA-mRNA network which composed of 10 up- and 3 down-regulated lncRNAs, 11 up- and 5 down-regulated miRNAs, 28 up- and 10 down-regulated mRNAs was constructed. Gene enrichment and pathway analysis revealed that the ceRNA network was associated with immune-related pathway and corresponding molecular function in patients who accepted IFN-α treatment. Next, we identified 3 most relevant to IFN-α treatment to HCC among these DE RNAs, namely FAM20A, IGFBP4 and MARCH3, as the prognostic associated genes for HCC. Furthermore, MARCH3 expression correlated with infiltrating levels of tumor infiltrating immune cells (TICCs) in HCC. MARCH3 expression also showed strong correlations with the gene markers of diverse immune cells in HCC. CONCLUSION: Our data discovered a novel ceRNA network in HCC patients receiving IFN-α therapy, which might lay the foundation for better understand the regulatory mechanism of IFN-α treatment.

Long noncoding RNA MALAT1 sponging miR-26a-5p to modulate Smad1 contributes to colorectal cancer progression by regulating autophagy.

Accumulating evidences have suggested that bone morphogenetic protein (BMP)-Smad have a functional role in regulating autophagy in the development of human colorectal cancer (CRC). However, the regulatory mechanisms controlling this process remain unclear. Here, we showed that Smad1, the key effector of BMP2-Smad signaling, induces autophagy by upregulating autophagy-related gene 5 (ATG5) expression, and Smad1 binds to the proximal promoter to induce its expression. Moreover, BMP2 induces autophagy in CRC. Overexpression of Smad1 promotes tumorigenesis and migration of CRC cells, and knockdown of ATG5 is able to rescue the Smad1-induced promotion of CRC proliferation and migration partially. Mechanistically, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) may act as a competing endogenous RNA by binding with miR-26a-5p competitively and thus modulating the de-repression of downstream target Smad1. Furthermore, clinical analysis results show that Smad1 is positively correlated with MALAT1 and negatively correlated with miR-26a-5p in CRC samples. In conclusion, our results demonstrated that Smad1 may serve as an oncogene in CRC through autophagy.

Comprehensive molecular profiling of intrahepatic cholangiocarcinoma in the Chinese population and therapeutic experience.

BACKGROUND: The genomic alterations of intrahepatic cholangiocarcinoma (ICC) in the Chinese population have not been fully revealed. Molecular profiling may provide a reference for clinical management, especially targeted therapy. METHODS: A retrospective study was conducted in 122 ICC patients. All patients' samples underwent next-generation sequencing (NGS), which analyzed 417 genes. The genetic characteristics, clinical management and therapeutic responses were analyzed. RESULTS: The most commonly mutated genes were TP53 (34%), KRAS (25%) and ARID1A (17%). Targeted agents were used referring to molecular profiling, in combination with chemotherapy. Twenty-two patients with wild-type KRAS/NRAS/BRAF were treated with cetuximab. The disease control and response rates were 78% and 47%, respectively, which were higher than those achieved with chemotherapy alone (72% and 11%, P = 0.16). Fifty-four patients underwent anti-VEGF treatment with bevacizumab. The disease control and response rates were 85% and 60%, respectively. Better therapeutic efficiency (P = 0.001) and longer progression-free survival (PFS) were observed in the bevacizumab-treated group compared to chemotherapy alone group (15.4 and 6.7 months, respectively; P = 0.04). The PFS of ten patients who underwent hepatectomy after combined treatment with chemotherapy and bevacizumab was longer than that of 139 patients who underwent surgical treatment (28.9 vs 18.0 months, P = 0.03). Two patients (1.6%) had signatures of microsatellite instability (MSI-H), and both benefited from immunotherapy. CONCLUSIONS: This study provides an overview of genetic alterations in Chinese ICC patients and indicates the potential clinical implications for NGS-based personalized therapies.

High glucose inhibits vascular endothelial Keap1/Nrf2/ARE signal pathway via downregulation of monomethyltransferase SET8 expression.

Hyperglycemia-mediated reactive oxygen species (ROS) accumulation plays an important role in hyperglycemia-induced endothelial injury. Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway inhibition participates in hyperglycemia-induced ROS accumulation. Our previous study indicated that SET8 overexpression inhibits high glucose-mediated ROS accumulation in human umbilical vein endothelial cells (HUVECs). In the present study, we hypothesize that SET8 may play a major role in high glucose-induced ROS accumulation via modulation of Keap1/Nrf2/ARE pathway. Our data indicated that high glucose mediated cell viability reduction, ROS accumulation, and Nrf2/ARE signal pathway inhibition via upregulation of Keap1 expression in HUVECs. Moreover, high glucose inhibited the expressions of SET8 and H4K20me1 (a downstream target of SET8). SET8 overexpression improved high glucose-mediated Keap1/Nrf2/ARE pathway inhibition and endothelial oxidation. Consistently, the effects of sh-SET8 were similar to that of high glucose treatment and were reversed by si-Keap1. A mechanistic study found that H4K20me1 was enriched at the Keap1 promoter region. SET8 overexpression attenuated Keap1 promoter activity and its expression, while mutant SET8 R259G did not affect Keap1 promoter activity and expression. The results of this study demonstrated that SET8 negatively regulates Keap1 expression, thus participating in high glucose-mediated Nrf2/ARE signal pathway inhibition and oxidative injury in HUVECs.

Fasting Induces Hepatocellular Carcinoma Cell Apoptosis by Inhibiting SET8 Expression.

BACKGROUND: Hepatocellular carcinoma (HCC) is a life-threatening cancer, and the Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signalling pathway plays a crucial role in apoptosis resistance in cancer cells. Fasting is reported to mediate tumour growth reduction and apoptosis. SET8 is involved in cancer proliferation, invasiveness, and migration. However, whether SET8 participates in fasting-mediated apoptosis in HCC remains unclear. METHODS: We used immunohistochemical staining to analyse the expression of SET8, Keap1, and Nrf2 in HCC tissues. Cell viability, apoptosis, and cellular reactive oxygen species (ROS) were assessed, and Western blot and qPCR analyses were used to examine the expression of Keap1/Nrf2 in HCC cells under fasting, SET8 overexpression, and PGC1α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1In vivo experiments were performed to verify the conclusions from the in vitro experiments. RESULTS: Our data indicate that SET8 expression is associated with poor survival in HCC patients. Both in vitro experiments. in vivo experiments were performed to verify the conclusions from the α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1. CONCLUSIONS: The results of our study demonstrate that fasting induces HCC apoptosis by inhibiting SET8 expression and that SET8 interacts with PGC1α to activate the Nrf2/ARE signalling pathway by inhibiting Keap1 expression.α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1.

Enhanced recovery after surgery program in the patients undergoing hepatectomy for benign liver lesions.

BACKGROUND: Enhanced recovery after surgery (ERAS) has shown effectiveness in terms of reducing the hospital stay and cost. However, the benefit of ERAS in patients undergoing hepatectomy for benign liver lesions is still unclear. METHODS: ERAS was implemented in our center since March 1st, 2018. From September 2016 to February 2018, 109 patients were enrolled into the control group, and from March 2018 to June 2019, 124 patients were enrolled into the ERAS group. All the indicators related to operation, liver functions, and postoperative outcomes were included in the analysis. RESULTS: The clinicopathologic baselines were similar in these two groups. A significantly higher proportion of patients underwent laparoscopic surgery in the ERAS group. On the whole, intraoperative blood loss (100.00 mL vs. 200.00 mL, P < 0.001), blood transfusion (3.23% vs. 10.09%, P = 0.033), total bilirubin (17.10 µmol/L vs. 21.00 µmol/L, P = 0.041), D-dimer (2.08 µg/mL vs. 2.57 µg/mL, P = 0.031), postoperative hospital stay (5.00 d vs. 6.00 d, P < 0.001), and postoperative morbidity (16.13% vs. 32.11%, P = 0.008) were significantly shorter or less in the ERAS group than those in the control group. After stratified by operation methods, ERAS group showed significantly shorter postoperative hospital stay in both open and laparoscopic operation (both P < 0.001). In patients underwent open surgery, ERAS group demonstrated significantly shorter operative duration (131.76 ± 8.75 min vs. 160.73 ± 7.23 min, P = 0.016), less intraoperative blood loss (200.00 mL vs. 450.00 mL, P = 0.008) and less postoperative morbidity (16.00% vs. 44.44%, P = 0.040). CONCLUSIONS: ERAS program may be safe and effective for the patients underwent hepatectomy, especially open surgery, for benign liver lesions.