application-mid-pancreatectomy-with-end-to-end-anastomosis-pancreatic

Application of Mid-Pancreatectomy with End-to-End Anastomosis in Pancreatic Benign Tumors

Mid-pancreatectomy combined with end-to-end anastomosis is a surgical procedure used to treat benign pancreatic tumors. It involves removing the tumor ...

application-robot-assisted-pancreaticobiliary-junction-resection

Application of Robot-assisted Pancreaticobiliary Junction Resection in Benign Duodenal Tumors

Robot-assisted pancreaticobiliary junction resection is a surgical technique employed to treat benign duodenal tumors. The procedure involves several key ...

Sun Yat-sen University

Thermal ablation is a main curative therapy for early-stage hepatocellular carcinoma (HCC). However, insufficient ablation has been shown to promote HCC progression. E3 ligases have been approved to play important roles in malignant tumors. Whether E3 ligases are involved in HCC progression caused by insufficient ablation remains unclear. Herein, using RNA-sequencing coupled with an in vitro loss-of-function screen, we found that the E3 ligase Neuronal Precursor cell-expressed Developmentally Downregulated 4 (Nedd4) was upregulated in HCC insufficient ablation tissues and promoted HCC cells migration. The upregulation of Nedd4 was induced by METTL14-mediated N-methyladenosine modification after sublethal heat treatment. Knockdown of Nedd4 inhibited HCC metastasis and growth in vitro and in vivo. Mechanistically, Nedd4 enhanced TGF-β signal transduction mediated tumor progression by directly binding to TGF-β type I receptor (TGFBR1) and forming K27-linked ubiquitin at Lysine 391. Additionally, the adverse effect on HCC of sublethal heat treatment was mediated by Nedd4. Clinically, high Nedd4 expression was positively correlated with aggressive tumor phenotypes and poor prognosis in HCC patients. Patient-derived xenograft (PDX) model confirmed this conclusion. Collectively, this study demonstrated that Nedd4 induced by insufficient ablation plays a crucial role in promoting HCC progression and provides a novel therapeutic target for HCC.

Insufficient ablation induces E3-ligase Nedd4 to promote hepatocellular carcinoma progression by tuning TGF-β signaling.

Recently, the albumin-bilirubin (ALBI) score, a continuous index consisting of only albumin and bilirubin, has been developed for objectively assessing liver function in patients with hepatocellular carcinoma (HCC). However, the ALBI score was arbitrarily categorized into three ALBI grades based on two artificially predetermined cutoff points with no explanation and statistical grounds, causing a considerable loss of discriminatory ability. This study aims to propose a modified ALBI (mALBI) grade for offering a detailed evaluation of hepatic reserve and specify its role during clinical practice in the HCC setting. The study population comprised 3540 HCC patients treated with mainstream therapies including hepatectomy (n=2056), thermal ablation (n=550), and transcatheter arterial chemoembolization (n=934) from 2002 to 2017. The ALBI score was stratified into four mALBI grades through a recently proposed statistical method aiming to select the optimal cutoff points of a continuous predictive variable by maximizing the discriminative ability in a multivariable Cox regression model. The mALBI grade had an overall better discriminatory ability than the ALBI grade in predicting overall survival through Harrell's C-index (0.614 vs. 0.598, P<0.001). Both visual inspections of Kaplan-Meier curves and calculation of hazard ratios displayed a more subtle evaluation of liver function using the mALBI grade. Moreover, the newly identified cut-point (ALBI score = -2.29) between the mALBI grade 2a and 2b was much closer to a 30% retention rate of indocyanine green at 15 minutes, an indicator for the performance of a subsegmentectomy. The newly proposed mALBI grade provides a more subtle assessment of liver function to guide clinical decision-making and predicts the prognosis of HCC patients more accurately than the original ALBI grade.

A detailed assessment of liver function in patients with hepatocellular carcinoma via the modified albumin-bilirubin (mALBI) grade.

Transarterial chemoembolization (TACE) is the major treatment for advanced hepatocellular carcinoma (HCC), but it may cause hypoxic environment, leading to rapid progression after treatment. Here, using high-throughput sequencing on different models, S100 calcium binding protein A9 (S100A9) is identified as a key oncogene involved in post-TACE progression. Depletion or pharmacologic inhibition of S100A9 significantly dampens the growth and metastatic ability of HCC. Mechanistically, TACE induces S100A9 via hypoxia-inducible factor 1α (HIF1A)-mediated pathway. S100A9 acts as a scaffold recruiting ubiquitin specific peptidase 10 and phosphoglycerate mutase family member 5 (PGAM5) to form a tripolymer, causing the deubiquitination and stabilization of PGAM5, leading to mitochondrial fission and reactive oxygen species production, thereby promoting the growth and metastasis of HCC. Higher S100A9 level in HCC tissue or in serum predicts a worse outcome for HCC patients. Collectively, this study identifies S100A9 as a key driver for post-TACE HCC progression. Targeting S100A9 may be a promising therapeutic strategy for HCC patients.

S100A9 Derived from Chemoembolization-Induced Hypoxia Governs Mitochondrial Function in Hepatocellular Carcinoma Progression.

Gastric cancer with liver metastasis (GCLM) is highly aggressive and has a poor prognosis. This study aims to evaluate the survival benefit of primary tumor resection (PTR) for gastric cancer with liver metastasis.

Survival benefit of primary tumor resection for gastric cancer with liver metastasis: A propensity score-matched, population-based study.

Although oxaliplatin-based chemotherapy has been effective in the treatment of hepatocellular carcinoma (HCC), primary or acquired resistance to oxaliplatin remains a major challenge in the clinic. Through functional screening using CRISPR/Cas9 activation library, transcriptomic profiling of clinical samples, and functional validation in vitro and in vivo, we identify PRMT3 as a key driver of oxaliplatin resistance. Mechanistically, PRMT3-mediated oxaliplatin-resistance is in part dependent on the methylation of IGF2BP1 at R452, which is critical for the function of IGF2BP1 in stabilizing the mRNA of HEG1, an effector of PRMT3-IGF2BP1 axis. Also, PRMT3 overexpression may serve as a biomarker for oxaliplatin resistance in HCC patients. Collectively, our study defines the PRTM3-IGF2BP1-HEG1 axis as important regulators and therapeutic targets in oxaliplatin-resistance and suggests the potential to use PRMT3 expression level in pretreatment biopsy as a biomarker for oxaliplatin-resistance in HCC patients.

PRMT3-mediated arginine methylation of IGF2BP1 promotes oxaliplatin resistance in liver cancer.

Metastasis is a major factor associated with high recurrence and mortality in hepatocellular carcinoma (HCC) patients while the underlying mechanism of metastasis remains elusive. In our study, procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) was shown to be involved in the process of metastasis in HCC.

Dysregulation of PLOD2 Promotes Tumor Metastasis and Invasion in Hepatocellular Carcinoma.

To evaluate whether this conversion rate to resectability could be increased when patients are treated with transarterial chemoembolization and hepatic arterial infusion chemotherapy (TACE-HAIC) using oxaliplatin plus fluorouracil/leucovorin.

Conversion to Resectability Using Transarterial Chemoembolization Combined With Hepatic Arterial Infusion Chemotherapy for Initially Unresectable Hepatocellular Carcinoma.

Although messenger RNA translation is tightly regulated to preserve protein synthesis and cellular homeostasis, chronic exposure to interferon-γ (IFN-γ) in several cancers can lead to tryptophan (Trp) shortage via the indoleamine-2,3-dioxygenase (IDO)- kynurenine pathway and therefore promotes the production of aberrant peptides by ribosomal frameshifting and tryptophan-to-phenylalanine (W>F) codon reassignment events (substitutants) specifically at Trp codons. However, the effect of Trp depletion on the generation of aberrant peptides by ribosomal mistranslation in gastric cancer (GC) is still obscure. Here, it is shows that the abundant infiltrating lymphocytes in EBV-positive GC continuously secreted IFN-γ, upregulated IDO1 expression, leading to Trp shortage and the induction of W>F substitutants. Intriguingly, the production of W>F substitutants in EBV-positive GC is linked to antigen presentation and the activation of the mTOR/eIF4E signaling pathway. Inhibiting either the mTOR/eIF4E pathway or EIF4E expression counteracted the production and antigen presentation of W>F substitutants. Thus, the mTOR/eIF4E pathway exposed the vulnerability of gastric cancer by accelerating the production of aberrant peptides and boosting immune activation through W>F substitutant events. This work proposes that EBV-positive GC patients with mTOR/eIF4E hyperactivation may benefit from anti-tumor immunotherapy.

Hyperactivation of mTOR/eIF4E Signaling Pathway Promotes the Production of Tryptophan-To-Phenylalanine Substitutants in EBV-Positive Gastric Cancer.

Monoacylglycerol acyltransferase-2 (MOGAT2), encodes MOGAT enzyme in the re-synthesis of triacylglycerol and protects from metabolism disorders. While, its precise involvement in colorectal cancer (CRC) progression remains inadequately understood. Our study demonstrated that knockout of Mogat2 in Apc mice expedited intestinal tumor growth and progression, indicating that Mogat2 plays a tumor-suppressing role in CRC. Mechanically, Mogat2 deletion resulted in a significant alter the gut microbiota, while Fecal Microbiota Transplantation (FMT) experiments demonstrated that the gut microbiota in Mogat2 deleted mice promoted tumor growth. Furthermore, we identified Mogat2 as a functional regulator suppressing CRC cell proliferation and tumor growth by inhibiting the NF-κB signaling pathway . Collectively, these results provide novel insights into the protective double roles of Mogat2, inhibiting of NF-κB pathway and keeping gut microbiota homeostasis in colorectal cancer, which may help the development of novel cancer treatments for CRC.

Monoacylglycerol acyltransferase-2 inhibits colorectal carcinogenesis in APC mice.

Sorafenib is a commonly used first-line kinase-targeted drug for advanced hepatocellular carcinoma (HCC) patients suffering from limited efficacy. Emerging evidence indicates that sorafenib exerts anti-cancer activity through the induction of ferroptosis in HCC cells, but the underlying mechanism is still unclear.

ArticleTotal : 2	Year
Publication title	2024
Publication title	2024

Article	Year
Insufficient ablation induces E3-ligase Nedd4 to promote hepatocellular carcinoma progression by tuning TGF-β signaling. Oncogene\| PubMed ID: 35501461	2022
A detailed assessment of liver function in patients with hepatocellular carcinoma via the modified albumin-bilirubin (mALBI) grade. American journal of cancer research\| PubMed ID: 35812041	2022
S100A9 Derived from Chemoembolization-Induced Hypoxia Governs Mitochondrial Function in Hepatocellular Carcinoma Progression. Advanced science (Weinheim, Baden-Wurttemberg, Germany)\| PubMed ID: 36041055	2022
Survival benefit of primary tumor resection for gastric cancer with liver metastasis: A propensity score-matched, population-based study. Frontiers in oncology\| PubMed ID: 36465378	2022
PRMT3-mediated arginine methylation of IGF2BP1 promotes oxaliplatin resistance in liver cancer. Nature communications\| PubMed ID: 37024475	2023
Dysregulation of PLOD2 Promotes Tumor Metastasis and Invasion in Hepatocellular Carcinoma. Journal of clinical and translational hepatology\| PubMed ID: 37577214	2023
Conversion to Resectability Using Transarterial Chemoembolization Combined With Hepatic Arterial Infusion Chemotherapy for Initially Unresectable Hepatocellular Carcinoma. Annals of surgery open : perspectives of surgical history, education, and clinical approaches\| PubMed ID: 37636551	2021
Hyperactivation of mTOR/eIF4E Signaling Pathway Promotes the Production of Tryptophan-To-Phenylalanine Substitutants in EBV-Positive Gastric Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany)\| PubMed ID: 38994917	2024
Monoacylglycerol acyltransferase-2 inhibits colorectal carcinogenesis in APC mice. iScience\| PubMed ID: 39055928	2024
Regulatory factor X1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by transcriptional regulation of BECN1. Cellular oncology (Dordrecht, Netherlands)\| PubMed ID: 39652303	2024

Chengrui Zhong

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