Germline Variants and Genetic Interactions of Several EMT Regulatory Genes Increase the Risk of HBV-Related Hepatocellular Carcinoma

Epithelial-mesenchymal transition (EMT) plays an important role in the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We hypothesized that germline variants in the major EMT regulatory genes (SNAIL1, ZEB1, ZEB2, TWIST1) may influence the development of HBV-related HCC. We included 421 cases of HBsAg-positive patients with HCC, 1371 cases of HBsAg-positive subjects without HCC [patients with chronic hepatitis B (CHB) or liver cirrhosis (LC)] and 618 cases of healthy controls in the case-control study. Genotype, allele, and haplotype associations in the major EMT regulatory genes were tested. Environment-gene and gene-gene interactions were analysed using the non-parametric model-free multifactor dimensionality reduction (MDR) method. The SNAIL1rs4647958T>C was associated with a significantly increased risk of both HCC (CT+CC vs. TT: OR=1.559; 95% confidence interval [CI], 1.073-2.264; P=0.020) and CHB+LC (CT+CC vs. TT: OR=1.509; 95% CI, 1.145-1.988; P=0.003). Carriers of the TWIST1rs2285681G>C (genotypes CT+CC) had an increased risk of HCC (CG+CC vs. GG: OR=1.407; 95% CI, 1.065-1.858; P=0.016). The ZEB2rs3806475T>C was associated with significantly increased risk of both HCC (Precessive =0.001) and CHB+LC (Precessive<0.001). The CG haplotype of the rs4647958/rs1543442 haplotype block was associated with significant differences between healthy subjects and HCC patients (P=0.0347). Meanwhile, the CT haplotype of the rs2285681/rs2285682 haplotype block was associated with significant differences between CHB+LC and HCC patients (P=0.0123). In MDR analysis, the combination of TWIST1rs2285681, ZEB2rs3806475, SNAIL1rs4647958 exhibited the most significant association with CHB+LC and Health control in the three-locus model. Our results suggest significant single-gene associations and environment-gene/gene-gene interactions of EMT-related genes with HBV-related HCC.

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Recent Advances: The Imbalance of Immune Cells and Cytokines in the Pathogenesis of Hepatocellular Carcinoma

Diagnostics ◽

10.3390/diagnostics10050338 ◽

2020 ◽

Vol 10 (5) ◽

pp. 338

Author(s):

Kumar Jayant ◽

Nagy Habib ◽

Kai W. Huang ◽

Jane Warwick ◽

Ramesh Arasaradnam

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Cells ◽

Epithelial Mesenchymal Transition ◽

Critical Role ◽

Liver Parenchyma ◽

Tumour Microenvironment ◽

Tumour Immunity ◽

Mesenchymal Transition ◽

Increased Risk ◽

Inflammatory State

Recent advancement in the immunological understanding of genesis of hepatocellular carcinoma (HCC) has implicated a decline in anti-tumour immunity on the background of chronic inflammatory state of liver parenchyma. The development of HCC involves a network of immunological activity in the tumour microenvironment involving continuous interaction between tumour and stromal cells. The reduction in anti-tumour immunity is secondary to changes in various immune cells and cytokines, and the tumour microenvironment plays a critical role in modulating the process of liver fibrosis, hepatocarcinogenesis, epithelial-mesenchymal transition (EMT), tumor invasion and metastasis. Thus, it is considered as one of primary factor behind the despicable tumour behavior and observed poor survival; along with increased risk of recurrence following treatment in HCC. The primary intent of the present review is to facilitate the understanding of the complex network of immunological interactions of various immune cells, cytokines and tumour cells associated with the development and progression of HCC.

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Hepatitis B virus x protein induces epithelial-mesenchymal transition of hepatocellular carcinoma cells by regulating long non-coding RNA

Virology Journal ◽

10.1186/s12985-017-0903-5 ◽

2017 ◽

Vol 14 (1) ◽

Cited By ~ 15

Author(s):

Yinji Jin ◽

Di Wu ◽

Weiwei Yang ◽

Mingjiao Weng ◽

Yafei Li ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Epithelial Mesenchymal Transition ◽

Carcinoma Cells ◽

X Protein ◽

Mesenchymal Transition ◽

Non Coding Rna ◽

B Virus ◽

Long Non Coding Rna

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The Mutations in the Enhancer I/X Promoter and X Gene Region Increased Risk for Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Infection

Gastroenterology ◽

10.1016/s0016-5085(11)64028-6 ◽

2011 ◽

Vol 140 (5) ◽

pp. S-973 ◽

Cited By ~ 1

Author(s):

Eun Young Cho ◽

Jun Young Lee ◽

Tae Hyeon Kim ◽

Se Jin Kim ◽

Haak Cheoul Kim

Keyword(s):

Hepatocellular Carcinoma ◽

Chronic Hepatitis ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Gene Region ◽

Hepatitis B Infection ◽

Chronic Hepatitis B Infection ◽

Increased Risk ◽

X Gene

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Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma

Gut ◽

10.1136/gut.2003.033324 ◽

2004 ◽

Vol 53 (10) ◽

pp. 1494-1498 ◽

Cited By ~ 322

Author(s):

H L-Y Chan

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Virus Infection ◽

Hepatitis B ◽

Hepatitis B Virus Infection ◽

Increased Risk ◽

B Virus ◽

Genotype C

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Hepatitis B virus X protein promotes epithelial‑mesenchymal transition and metastasis in hepatocellular carcinoma cell line HCCLM3 by targeting HMGA2

Oncology Letters ◽

10.3892/ol.2018.9359 ◽

2018 ◽

Cited By ~ 1

Author(s):

Yong Zha ◽

Qian Yao ◽

Jin‑Sheng Liu ◽

Yuan‑Yuan Wang ◽

Wei‑Ming Sun

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Cell Line ◽

Epithelial Mesenchymal Transition ◽

Carcinoma Cell ◽

Mesenchymal Transition ◽

B Virus ◽

Hepatocellular Carcinoma Cell Line ◽

Hepatocellular Carcinoma Cell

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Follow-Up Liver Stiffness Measurements after Liver Resection Influence Oncologic Outcomes of Hepatitis-B-Associated Hepatocellular Carcinoma with Liver Cirrhosis

Cancers ◽

10.3390/cancers11030425 ◽

2019 ◽

Vol 11 (3) ◽

pp. 425 ◽

Cited By ~ 1

Author(s):

Jung Lee ◽

Hyun Lee ◽

Seung Kim ◽

Sang Ahn ◽

Kwan Lee

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cirrhosis ◽

Hepatitis B ◽

Antiviral Therapy ◽

Liver Stiffness ◽

Late Recurrence ◽

Oncologic Outcomes ◽

Increased Risk ◽

Hcc Recurrence

The severity of liver fibrosis can be noninvasively evaluated by measuring liver stiffness (LS) using transient elastography. This study aimed to evaluate the prognostic value of achieving low liver stiffness measurement (LSM) in patients with cirrhosis confirmed from the resected liver due to hepatocellular carcinoma (HCC). A total of 184 patients that received curative surgery for HCC related to the hepatitis B virus at Barcelona Clinic Liver Cancer stage 0–A, and had a METAVIR fibrosis score of 4 were investigated. LSM significantly decreased after antiviral therapy during follow-up (p = 0.001), and achieving LSM ≤8 kilopascal (kPa) suggested a reduced risk of late recurrence (>12 months) (hazard ratio (HR), 0.519; 95% confidence interval (CI), 0.307–0.877; p = 0.014). Older age at surgery (≥45 years) and multiple HCC nodules predicted an increased risk of late recurrence (HR, 3.270; 95% CI, 1.296–8.251; p = 0.012; and HR, 3.146; 95% CI, 1.396–7.089; p = 0.006). Decreased LSM also suggested decreased mortality (HR, 0.251; 95% CI, 0.086–0.756; p = 0.045) along with baseline low aspartate aminotransferase-to-platelet ratio index (APRI) score (<1.5) (HR, 0.251; 95% CI, 0.086–0.759; p = 0.041). Having early HCC recurrence (HR, 9.416; 95% CI, 3.566–24.861; p < 0.001) and microvascular tumor invasion (HR, 3.191; 95% CI, 1.188–8.568; p = 0.021) predicted increased mortality. Among HCC patients with liver cirrhosis under antiviral therapy, achieving low LSM (≤8 kPa) predicted reduced late HCC recurrence.

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