complete-laparoscopic-radical-resection-perihilar-cholangiocarcinoma

Complete Laparoscopic Radical Resection of Perihilar Cholangiocarcinoma Type IIIb

Perihilar cholangiocarcinoma (pCCA) is a highly malignant and aggressive tumor, with radical resection being the only curative treatment available. With ...

the second affiliated hospital of nanchang university

Jiangxi Province Engineering Research Center of Hepatobiliary Disease

To explore the therapeutic significance and indications of pulmonary metastasectomy (PMT) in hepatocellular carcinoma (HCC) patients with pulmonary metastasis (PM) following liver resection (LR).

Therapeutic significance and indications of pulmonary metastasectomy for hepatocellular carcinoma following liver resection.

Hepatitis B virus X protein (HBx) is involved in the initiation and progression of hepatocellular carcinoma (HCC) by regulating the host protein-coding genes. In this study, we showed that HBx altered the expression of lncRNAs to promote the progression of HCC. lncRNA microarray and quantitative reverse-transcription polymerase chain reactions (qRT-PCRs) were performed to identify lncRNAs that were differentially regulated by HBx in HCC cells and tissues. Protein, mRNA, and lncRNA expression analyses; cell cycle and apoptosis analyses; loss/gain-of-function analysis were performed to delineate the consequences of WEE2-AS1 upregulation in HCC cells. WEE2-AS1 over-expressed in HCC and was positively correlated to hepatitis B virus (HBV) infection, hepatic vascular invasion, poor tumor differentiation and poor patient prognosis. WEE2-AS1 also accelerated the proliferation, migration, invasion and cell cycle progression of HCC cells. Fermitin family member 3 (FERMT3) was a downstream target of WEE2-AS1. In conclusion, there is a preliminary HBx-WEE2-AS1- FERMT3 pathway which may serve as a therapeutic target for HBV-associated HCC.

Hepatitis B virus X protein related lncRNA WEE2-AS1 promotes hepatocellular carcinoma proliferation and invasion.

BACKGROUND: Tumor metastasis is the major reason for poor prognosis of hepatocellular carcinoma (HCC) patients after hepatic resection. SMYD3 has been demonstrated to promote liver tumor metastasis in mice. However, the detailed molecular mechanism is still largely unknown.

ANKHD1 is required for SMYD3 to promote tumor metastasis in hepatocellular carcinoma.

Recent studies have shown that the expression levels of glucose-regulated protein 78 (GRP78) and homeobox B9 (HOXB9) are both upregulated in hepatocellular carcinoma (HCC) and are closely related to HCC invasion and metastasis. However, whether there is a regulatory relationship between GRP78 and HOXB9 is unclear. In this study, we examined the expression of GRP78 and HOXB9 in HCC tissues and adjacent nontumor tissues. Correlation analysis indicated that GRP78 and HOXB9 expression were positively correlated. High levels of GRP78 and HOXB9 expression are closely related to worse clinicopathological features. Knockdown of GRP78 in HCC cells decreased the mRNA and protein expression of HOXB9, but increase HOXB9 expression reversed the decrease in invasion and metastasis induced by knocking down GRP78. Further experiments showed that GRP78 regulates HOXB9 through the Wnt signaling pathway by chaperoning low-density lipoprotein receptor-related protein 6 (LRP6). Importantly, we found that GPR78 promoted maturation of LRP6, while knockdown of GRP78 led to LRP6 misfolding and endoplasmic reticulum-associated degradation (ERAD). Consequently, the levels of mature LRP6 were reduced, and Wnt/HOXB9 signaling was inhibited. Our data suggest that the GRP78-LRP6-HOXB9 axis regulates the invasion and metastasis of HCC and may represent a potential therapeutic target for the treatment of HCC.

GRP78 activates the Wnt/HOXB9 pathway to promote invasion and metastasis of hepatocellular carcinoma by chaperoning LRP6.

Changes in immune responses to hepatocellular carcinoma (HCC) are closely related to the occurrence, development, and prognosis of this disease. Exploring the role of immune-related genes (IRGs) in HCC would provide insights into the mechanisms regulating this disease. The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) provide a platform for such research, owing to a large number of HCC samples available for comprehensive and systematic immunogenomics analyses. We analyzed the IRGs expression profile and clinical information of patients with HCC based on the TCGA and ICGC database. Potential molecular mechanisms and properties of the screened IRGs were analyzed across multiple databases. And we analyzed the correlation between IRGs, single-nucleotide polymorphisms, and copy number variation. A novel prognostic index, based on IRGs, was developed using the LASSO Cox regression algorithm, followed by univariate and multivariate Cox regression analyses to analyze the prognostic index. Information in the ICGC database was used to verify the reliability of the prognostic index. A total of 54 differentially expressed IRGs were found to be significantly associated with HCC prognosis, and there is a significant correlation between their expression level and copy number variation. Functional enrichment analyses indicated that the genes play active roles in tumor and immune-related signaling pathways. In addition, five potential biomarkers namely IRG, MAPK3, HSP90AA1, HSP90AB1, HSPA4, and CDK4, were identified. Finally, a novel prognostic index, based on IRGs (PSMD14, FABP6, ISG20L2, HGF, BIRC5, IL17D, and STC2), was found useful as an independent prognostic factor, not only for prognosis but also to reflect levels of infiltration in a variety of immune cells. Our team conducted a genomics study of IRGs in HCC and screened several clinically significant IRGs, and our model provides an effective approach for stratification and characterization of patients using IRG-based immunolabeling tools to monitor the prognosis of HCC.

A novel prognostic index of hepatocellular carcinoma based on immunogenomic landscape analysis.

The dysregulation of deubiquitinating enzymes (DUBs), which regulate the stability of most cellular proteins, has been implicated in many human diseases, including cancers. Thus, DUBs can be considered potential therapeutic targets for many cancers. However, the role of deubiquitinase ubiquitin-specific protease 18 (USP18) in pancreatic cancer remains unknown. Here, we found that the deubiquitinase ubiquitin-specific protease 18 (USP18) is significantly upregulated in pancreatic cancer and is correlated with a shorter median overall and relapse-free survival. A functional assay demonstrated that overexpression of USP18 resulted in increased proliferation of pancreatic cancer cells. Conversely, these phenomena were reversed after USP18 was silenced in pancreatic cancer cells. Further investigation revealed that USP18 promoted cell progression by increasing c-Myc expression, which has been reported to control pancreatic cancer progression, and our data demonstrated that c-Myc is key for USP18-mediated pancreatic cancer cell progression  and . Moreover, we found that USP18 promoted pancreatic cancer progression via upregulation of Notch-1-dependent c-Myc. Mechanistically, USP18 interacts with and removes K48-linked ubiquitin chains from Notch1, thereby stabilizing Notch1 and promoting the Notch1-c-Myc pathway. Our work identifies and validates USP18 as a pancreatic cancer oncogene and provides a potential druggable target for this intractable disease.

Deubiquitinase USP18 promotes the progression of pancreatic cancer via enhancing the Notch1-c-Myc axis.

The HSP70 family of heat shock protein plays a critical role in protein synthesis and transport to maintain protein homeostasis. Several studies have indicated that HSP70s are related to the development and occurrence of various cancers.

The expression profiles and prognostic values of HSP70s in hepatocellular carcinoma.

 This study aims to establish an effective nomogram to predict the overall survival of patients with intrahepatic cholangiocarcinoma (ICC).  Data used to build the nomogram comes from the Surveillance, Epidemiology, and End Results (SEER) database. Patients diagnosed with ICC between 2005 and 2016 were retrospectively collected. Prediction accuracy and discrimination ability of the nomogram was evaluated by concordance index (C-index) and calibration curve. The area under receiver operating characteristic (ROC) curve (AUC) and decision curve analysis (DCA) were used to compare the precision of the 1-, 3-, and 5-year survival of the nomogram with 8th American Joint Commission on Cancer (AJCC) tumor-node-metastasis (TNM) staging system. Finally, it was verified in a prospective study of patients diagnosed with ICC in the Second Affiliated Hospital of Nanchang University from 2013 to 2020 by bootstrap resampling.  The study contains two parts of data; we establish a nomogram using external data, and we conducted internal verification and external verification. The nomogram that we have established has good calibration, with a concordance index (C-index) of 0.75 (95% CI, 0.74-0.76) for overall survival (OS) prediction. The AUC value of the nomogram predicting 1-, 3-, and 5-year OS rates were 0.821, 0.828, and 0.836, which were higher than those of the 8th AJCC TNM staging systems. The calibration curve for the probability of survival between prediction by nomogram and actual observation shows good agreement. The nomogram showed better accuracy than the 8th edition AJCC TNM staging.  The nomogram established can provide a more accurate prognosis for patients with intrahepatic cholangiocarcinoma.

Development and Validation a Nomogram for Predicting Overall Survival in Patients With Intrahepatic Cholangiocarcinoma.

 The aim of this study based on log odds of positive lymph nodes (LODDS) is to develop and validate an effective prognostic nomogram for patients with T3 and T4 gallbladder cancer (GBC) after resection.  A total of 728 T3 and T4 gallbladder cancer patients after resection from the Surveillance, Epidemiology, and End Results (SEER) database, randomly divided into training cohort and validation cohort according to 7:3. Another 128 patients from The Second Affiliated Hospital of Nanchang University for external validation. The nomograms were built by the Cox regression model and the Fine and Grey's model. Concordance index (C-index), calibration curve and the area under receiver operating characteristic (ROC) curve (AUC) were used to evaluate the nomogram and internal verification. The decision curve analysis (DCA) was used to measure clinical applicability.  LODDS was independent prognostic predictor for overall survival (OS) and cancer-specific survival (CSS), and established the nomograms on this basis. The nomogram we have established has a good evaluation effect, with a C-index of 0.719 (95%CI, 0.707-0.731) for OS and 0.747 (95%CI, 0.733-0.760) for CSS. The calibration curves of OS and CSS both showed good calibration capability, and the AUC for predicting 1-, 2-, and 3-year 0.858, 0.848 were and 0.811 for OS, and 0.794, 0.793, and 0.750 for CSS. The DCA of nomograms both showed good clinical applicability.  The nomogram can provide effective OS and CSS prediction for patients with advanced gallbladder cancer after surgery.

Nomogram Based on Log Odds of Positive Lymph Nodes Predicting Cancer-Specific Survival in Patients With T3 and T4 Gallbladder Cancer After Radical Resection.

RRP12 (ribosomal RNA processing 12 homolog) is a nucleolar protein involved in the maturation and transport of eukaryotic ribosomal subunits and is a type of RNA binding protein. In recent years, considerable research has indicated that RRP12 is associated with the occurrence and development of multiple cancers. However, there is no research on RRP12 in hepatocellular carcinoma. Herein, we aimed to explore the role and significance of RRP12 in hepatocellular carcinoma.We used the TIMER and GEPIA databases to perform pan-cancer analyses of RRP12. The impact of RRP12 on the prognosis was analyzed through the GEPIA database. The relationship between RRP12 and immune cell infiltration was investigated by TIMER and GEPIA databases. Moreover, the expression of RRP12 in various liver cancer cells was evaluated by Western Blot to determine the cell line for the next experiment. Scratch test, Transwell test, and Edu tests were applied to validate the effects of RRP12 on the function of liver cancer cells. And the data were statistically analyzed.Pan-cancer analysis found that RPP12 was significantly upregulated in many cancers. Moreover, the prognostic analysis revealed that the difference in the expression of RRP12 has statistical significance for the overall survival rate and disease-free survival rate of liver cancer patients. In order to analyze the correlation between the expression level of RRP12 and clinical parameters, it was found that there was a significant negative correlation with tumor stage, tumor grade and tumor size. Univariate and multivariate analysis showed that RRP12 could be used as an independent prognostic factor for patients with hepatocellular carcinoma. Cellular experiments have proved that knocking down RRP12 can inhibit the proliferation, invasion, and metastasis of liver cancer cells.Therefore, RRP12 significantly affects the occurrence and development of HCC. Hence, RRP12 can become a potential target and prognostic biomarker for the treatment of hepatocellular carcinoma.

Validating RRP12 Expression and Its Prognostic Significance in HCC Based on Data Mining and Bioinformatics Methods.

Pancreatic cancer (PC) is one of the deadliest malignant tumors, and its resistance to gemcitabine chemotherapy is the primary reason for poor prognosis in patients. Ubiquitin-like protein FAT10 has recently been reported to promote tumor chemotherapy resistance. In this study, the expression of FAT10 in PC was significantly higher than that in adjacent noncancerous tissues. Increased expression of FAT10 in PC was related to a late TNM stage and decreased overall survival. Functional experiments revealed that downregulating the expression of FAT10 inhibits the proliferation and epithelial-mesenchymal transition (EMT) of PC cells, promotes the apoptosis of PC cells, and enhances sensitivity to gemcitabine chemotherapy. In addition, upregulation of FAT10 increased the expression of FOXM1 protein. The effect of downregulating FAT10 was reversed by FOXM1 overexpression, and FOXM1 knockdown inhibited EMT driven by FAT10 overexpression. Mechanistically, FAT10 stabilized the expression of FOXM1 by competing with ubiquitin to bind FOXM1 and inhibiting the ubiquitination-mediated degradation of FOXM1. In conclusion, the FAT10-FOXM1 axis is a pivotal driver of PC proliferation and gemcitabine resistance, and the results provide novel insights into chemotherapy resistance in PC.

FAT10 promotes chemotherapeutic resistance in pancreatic cancer by inducing epithelial-mesenchymal transition via stabilization of FOXM1 expression.

To explore the surgical risk factors of laparoscopic left-sided hepatectomy for hepatolithiasis and establish and validate a nomogram to estimate the corresponding surgical risks.

Nomogram predicting surgical risk of laparoscopic left-sided hepatectomy for hepatolithiasis.

Most patients with intrahepatic cholangiocarcinoma (ICC) have developed distant metastasis at the time of diagnosis, while there is rear related nomogram to predict the prognosis.

Establishment and external validation of prognosis prediction nomogram for patients with distant metastatic intrahepatic cholangiocarcinoma: based on a large population.

Article	Year
Therapeutic significance and indications of pulmonary metastasectomy for hepatocellular carcinoma following liver resection. International journal of surgery (London, England)\| PubMed ID: 28987561	2017
Hepatitis B virus X protein related lncRNA WEE2-AS1 promotes hepatocellular carcinoma proliferation and invasion. Biochemical and biophysical research communications\| PubMed ID: 30471857	2019
ANKHD1 is required for SMYD3 to promote tumor metastasis in hepatocellular carcinoma. Journal of experimental & clinical cancer research : CR\| PubMed ID: 30646949	2019
GRP78 activates the Wnt/HOXB9 pathway to promote invasion and metastasis of hepatocellular carcinoma by chaperoning LRP6. Experimental cell research\| PubMed ID: 31310747	2019
A novel prognostic index of hepatocellular carcinoma based on immunogenomic landscape analysis. Journal of cellular physiology\| PubMed ID: 32853412	2021
Deubiquitinase USP18 promotes the progression of pancreatic cancer via enhancing the Notch1-c-Myc axis. Aging\| PubMed ID: 33051403	2020
The expression profiles and prognostic values of HSP70s in hepatocellular carcinoma. Cancer cell international\| PubMed ID: 34059060	2021
Development and Validation a Nomogram for Predicting Overall Survival in Patients With Intrahepatic Cholangiocarcinoma. Frontiers in surgery\| PubMed ID: 34079814	2021
Nomogram Based on Log Odds of Positive Lymph Nodes Predicting Cancer-Specific Survival in Patients With T3 and T4 Gallbladder Cancer After Radical Resection. Frontiers in surgery\| PubMed ID: 34778352	2021
Validating RRP12 Expression and Its Prognostic Significance in HCC Based on Data Mining and Bioinformatics Methods. Frontiers in oncology\| PubMed ID: 35178347	2022
FAT10 promotes chemotherapeutic resistance in pancreatic cancer by inducing epithelial-mesenchymal transition via stabilization of FOXM1 expression. Cell death & disease\| PubMed ID: 35614040	2022
Nomogram predicting surgical risk of laparoscopic left-sided hepatectomy for hepatolithiasis. Langenbeck's archives of surgery\| PubMed ID: 37704787	2023
Establishment and external validation of prognosis prediction nomogram for patients with distant metastatic intrahepatic cholangiocarcinoma: based on a large population. BMC cancer\| PubMed ID: 38365630	2024

Zhigang Hu

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