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

Anoikis is a programmed death of cell induced upon detachment from the extracellular matrix (ECM). Resistance to anoikis is a critical contributor to cancer invasion and metastasis. High frequency of metastatic recurrence is a huge challenge for current therapy of hepatocellular carcinoma (HCC). Our previous study had identified sulfhydryl oxidase 1 (QSOX1) as a suppressor of HCC metastasis. In the present study, we used the anchorage-independent growth condition to mimic the detachment of HCC cells from ECM. We found that QSOX1 was induced in HCC cells under the anchorage-independent growth condition and that could be blocked by endoplasmic reticulum stress (ERS) inhibitor. Overexpression and knockdown of QSOX1 gene were performed on HCC cells. QSOX1 inhibited de novo synthesis of fatty acids (FAs) and cholesterol (ChE) and reduced their content in the detached HCC cells, and thus mediated mitochondrial apoptosis of HCC cells. In conclusion, QSOX1 is induced under detached culture condition via ERS. QSOX1 promotes mitochondrial apoptosis by suppressing the lipid synthesis of HCC cells in detached condition. QSOX1 appears to accelerate anoikis of HCC cells. These findings offer a new insight into how to overcome anoikis resistance of HCC cells and provide a potential target for prevention of HCC metastasis.

QSOX1 promotes mitochondrial apoptosis of hepatocellular carcinoma cells during anchorage-independent growth by inhibiting lipid synthesis.

Association of intrinsic pathways with altered tumor immune infiltration in hepatocellular carcinoma: New targets for combining immune therapy.

GOLM1, a type II transmembrane protein, is associated with tumor progression, metastasis and immunosuppression. However, the relationship between GOLM1 and the immunosuppressive molecule PD-L1 in HCC remains largely unclear. Here, we revealed that GOLM1 acts as a novel positive regulator of PD-L1, whose abnormal expression plays a crucial role in cancer immune evasion and progression. We found that GOLM1 is overexpressed and positively correlated with PD-L1 expression in HCC. Mechanistically, we found that GOLM1 promotes the phosphorylation of STAT3 by enhancing the level of EGFR, which in turn upregulates the transcriptional expression of PD-L1. Taken together, we demonstrated that GOLM1 acts as a positive regulator of PD-L1 expression via the EGFR/STAT3 signaling pathway in human HCC cells. This study provides a new insight into the regulatory mechanism of PD-L1 expression in HCC, which may provide a novel therapeutic target for HCC immunotherapy.

GOLM1 upregulates expression of PD-L1 through EGFR/STAT3 pathway in hepatocellular carcinoma.

Cholangiocarcinoma was a highly malignant liver cancer with poor prognosis, and immune infiltration status was considered an important factor in response to immunotherapy. In this investigation, we tried to locate immune infiltration related genes of cholangiocarcinoma through combination of bulk-sequencing and single-cell sequencing technology.

PNOC Expressed by B Cells in Cholangiocarcinoma Was Survival Related and LAIR2 Could Be a T Cell Exhaustion Biomarker in Tumor Microenvironment: Characterization of Immune Microenvironment Combining Single-Cell and Bulk Sequencing Technology.

Although the treatment of hepatocellular carcinoma (HCC) has been revolutionized by the advent of effective systemic therapies, the prognosis of patients with HCC remains dismal. Herein, we examined the pathophysiological role of PARG and assessed the utility of targeting dePARylation for HCC therapy.

PARG inhibition limits HCC progression and potentiates the efficacy of immune checkpoint therapy.

Autophagy in tumor was also found to influence immune microenvironment. The relation between autophagy and cancer intrinsic PD1 and PD-L1 expression was not clear.

Tumor-derived PD1 and PD-L1 could promote hepatocellular carcinoma growth through autophagy induction in vitro.

Cell adhesion molecule cluster of differentiation 44 (CD44) plays a significant role in cancer cell local invasion, intravasation, migration, and the establishment of metastatic lesions. However, little is known about the underlying mechanism of how CD44 regulates hepatocellular carcinoma (HCC) extrahepatic metastasis (EHM).

CD44 potentiates hepatocellular carcinoma migration and extrahepatic metastases via the AKT/ERK signaling CXCR4 axis.

Colorectal cancer (CRC) is one of the most prominent malignant diseases, with a high incidence and a dismal prognosis. Metastasis to the liver is the leading cause of death in CRC patients. This study aimed to identify accurate metastatic biomarkers of CRC and investigate the potential molecular mechanisms of liver metastasis of colorectal cancer (LMCRC).

Complement C5 is a novel biomarker for liver metastasis of colorectal cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality globally with limited effective treatment options. Although the combination of immunotherapy and chemotherapy has been attempted in clinical trials to treat PDAC, the results are not promising. Therefore, in this study, we explored the application of a novel combination strategy with disulfiram (DSF) to enhance the treatment efficacy of PDAC as well as its underlying molecular mechanism. We compared the antitumor effects between single agents and the combination therapy by using mouse allograft tumor model and found DSF combined with chemoimmunotherapy significantly suppressed the growth of subcutaneous PDAC allograft tumor in mice and prolonged the survival of mice. To further investigate the alterations in the immune microenvironment of tumors from different treatment groups, we employed flow cytometry and RNA-seq analysis to examine the composition of tumor-infiltrating immune cells as well as the expression level of a variety of cytokines. Our results revealed that the proportion of CD8 T cells was notably elevated and that multiple cytokines were upregulated in the combination therapy group. Furthermore, qRT-PCR results indicated that DSF could upregulate the mRNA levels of IFNα and IFNβ, which could be reversed by STING pathway inhibitor. Mechanistically, we found that DSF activated STING signaling pathway through Poly (ADP-ribose) polymerases (PARP1) inhibition. Taken together, our findings highlight the potential clinical application of this novel combination strategy using DSF and chemoimmunotherapy in the treatment of patients with PDAC.

Disulfiram combined with chemoimmunotherapy potentiates pancreatic cancer treatment efficacy through the activation of cGAS-STING signaling pathway via suppressing PARP1 expression.

Exosomes (EXOs) are considered natural nanoparticles which have been widely used as carriers for the treatment and diagnosis of various diseases. However, due to the non-specific uptake, the unmodified EXOs cannot effectively deliver the vector to the target site. In this study, we used pDisplay vector to engineer Glypican-3 (GPC3) single-chain scFv antibody to the exosome surface, and the effect of engineered exosomes on the proliferation and migration of hepatocellular carcinoma (HCC) cells was determined by a series of in vitro experiments as well as in vivo mouse xenograft model and PDX model. Furthermore, we established an improved delivery system by engineering single-chain scFv antibody against GPC3 on the EXO surface for a more efficient HCC targeting. Moreover, the delivery system was loaded with IR780 and Lenvatinib for a combination of thermotherapy and chemotherapy. Our results revealed that the antibody-engineered exosomes enabled rapid imaging of HCC xenograft models post IR780 loading and showed significant anti-tumor photothermal therapy (PTT) effects after irradiation. Since dual loading of IR780 and Lenvatinib in exosomes required only a single injection and had a maximal efficacy against cancer cells, our findings highlight the clinical application of using GPC3 single-chain scFv antibody-engineered exosomes loaded with IR780 and Lenvartinib to achieve the imaging and the treatment of HCC from the combined effect of IR780-induced PTT and Lenvatinib-induced chemotherapy.

Exosomes with IR780 and Lenvatinib loaded on GPC3 single-chain scFv antibodies for targeted hyperthermia and chemotherapy in hepatocellular carcinoma therapy.

The effectiveness of immune checkpoint inhibitor (ICI) therapy for hepatocellular carcinoma (HCC) is limited by treatment resistance. However, the mechanisms underlying immunotherapy resistance remain elusive. We aimed to identify the role of CT10 regulator of kinase-like (CRKL) in resistance to anti-PD-1 therapy in HCC.

CRKL dictates anti-PD-1 resistance by mediating tumor-associated neutrophil infiltration in hepatocellular carcinoma.

Exploring novel early detection biomarkers and developing more efficacious treatments remain pressing tasks in the current research landscape for hepatocellular carcinoma (HCC). Morphologically and molecularly separate from apoptosis, cell death, and autophagy, ferroptosis is a recently discovered, unique, controlled form of cell death. SLC7A11 (also known as xCT) represents a subunit of the cystine-glutamate antiporter (also known as system Xc(-)). A growing body of research suggests that induction of ferroptosis through SLC7A11 can effectively eliminate hepatocellular carcinoma (HCC) cells, particularly those exhibiting resistance to alternative forms of cell death. Thus, targeting ferroptosis via SLC7A11 may become a new direction for the design of therapeutic strategies for HCC. Although many research articles have investigated the possible roles of SLC7A11 in HCC, a study that summarizes the main findings, including the regulators and mechanisms of action of SLC7A11 in HCC is not available. Therefore, we present a comprehensive overview of the functions of ferroptosis, particularly SLC7A11, in the identification, development, and management of HCC in this review. In addition, we discuss how this knowledge can be translated into treatment by providing a systemic therapy in advanced HCC using sorafenib, the first-line drug targeting multiple kinases and SLC7A11. We further dissect the possible barriers as well as the corresponding solutions and provide insights on how to navigate effective treatment using this knowledge.

SLC7A11 in hepatocellular carcinoma: potential mechanisms, regulation, and clinical significance.

Functional roles of SIGLEC15 in hepatocellular carcinoma (HCC) were not clear, which was recently found to be an immune inhibitor with similar structure of inhibitory B7 family members. SIGLEC15 expression in HCC was explored in public databases and further examined by PCR analysis. SIGLEC15 and PD-L1 expression patterns were examined in HCC samples through immunohistochemistry. SIGLEC15 expression was knocked-down or over-expressed in HCC cell lines, and CCK8 tests were used to examine cell proliferative ability in vitro. Influences of SIGLEC15 expression on tumor growth were examined in immune deficient and immunocompetent mice respectively. Co-culture system of HCC cell lines and Jurkat cells, flow cytometry analysis of tumor infiltrated immune cells and further sequencing analyses were performed to investigate how SIGLEC15 could affect T cells in vitro and in vivo. We found SIGLEC15 was increased in HCC tumor tissues and was negatively correlated with PD-L1 in HCC samples. In vitro and in vivo models demonstrated inhibition of SIGLEC15 did not directly influence tumor proliferation. However, SIGLEC15 could promoted HCC immune evasion in immune competent mouse models. Knock-out of  could inhibit tumor growth and reinvigorate CD8+ T cell cytotoxicity. Anti-SIGLEC15 treatment could effectively inhibit tumor growth in mouse models with or without mononuclear phagocyte deletion. Bulk and single-cell RNA sequencing data of treated mouse tumors demonstrated SIGLEC15 could interfere CD8+ T cell viability and induce cell apoptosis. In all, SIGLEC15 was negatively correlated with PD-L1 in HCC and mainly promote HCC immune evasion through inhibition of CD8+ T cell viability and cytotoxicity.

Article	Year
QSOX1 promotes mitochondrial apoptosis of hepatocellular carcinoma cells during anchorage-independent growth by inhibiting lipid synthesis. Biochemical and biophysical research communications\| PubMed ID: 32863002	2020
Association of intrinsic pathways with altered tumor immune infiltration in hepatocellular carcinoma: New targets for combining immune therapy. Clinical and translational medicine\| PubMed ID: 33252850	2020
GOLM1 upregulates expression of PD-L1 through EGFR/STAT3 pathway in hepatocellular carcinoma. American journal of cancer research\| PubMed ID: 33294262	2020
PNOC Expressed by B Cells in Cholangiocarcinoma Was Survival Related and LAIR2 Could Be a T Cell Exhaustion Biomarker in Tumor Microenvironment: Characterization of Immune Microenvironment C... Frontiers in immunology\| PubMed ID: 33841428	2021
PARG inhibition limits HCC progression and potentiates the efficacy of immune checkpoint therapy. Journal of hepatology\| PubMed ID: 35157958	2022
Tumor-derived PD1 and PD-L1 could promote hepatocellular carcinoma growth through autophagy induction in vitro. Biochemical and biophysical research communications\| PubMed ID: 35316767	2022
CD44 potentiates hepatocellular carcinoma migration and extrahepatic metastases via the AKT/ERK signaling CXCR4 axis. Annals of translational medicine\| PubMed ID: 35845518	2022
Complement C5 is a novel biomarker for liver metastasis of colorectal cancer. Journal of gastrointestinal oncology\| PubMed ID: 36388659	2022
Disulfiram combined with chemoimmunotherapy potentiates pancreatic cancer treatment efficacy through the activation of cGAS-STING signaling pathway via suppressing PARP1 expression. American journal of cancer research\| PubMed ID: 37293156	2023
Exosomes with IR780 and Lenvatinib loaded on GPC3 single-chain scFv antibodies for targeted hyperthermia and chemotherapy in hepatocellular carcinoma therapy. American journal of cancer research\| PubMed ID: 38058824	2023
CRKL dictates anti-PD-1 resistance by mediating tumor-associated neutrophil infiltration in hepatocellular carcinoma. Journal of hepatology\| PubMed ID: 38403027	2024
SLC7A11 in hepatocellular carcinoma: potential mechanisms, regulation, and clinical significance. American journal of cancer research\| PubMed ID: 38859833	2024
SIGLEC15, negatively correlated with PD-L1 in HCC, could induce CD8+ T cell apoptosis to promote immune evasion. Oncoimmunology\| PubMed ID: 38988824	2024

Binghai Zhou

Biography

JoVE Journal Publications

Other Publications