Downregulation of LncRNA GCLC-1 Promotes Microcystin-LR-Induced Malignant Transformation of Human Liver Cells by Regulating GCLC Expression.

Microcystin-LR (MCLR) is an aquatic toxin, which could lead to the development of hepatocellular carcinoma (HCC). Long non-coding RNAs (lncRNAs) are considered important regulatory elements in the occurrence and development of cancer. However, the roles and mechanisms of lncRNAs during the process of HCC, induced by MCLR, remain elusive. Here, we identified a novel lncRNA, namely lnc-GCLC-1 (lncGCLC), which is in close proximity to the chromosome location of glutamate-cysteine ligase catalytic subunit (GCLC). We then investigated the role of lncGCLC in MCLR-induced malignant transformation of WRL68, a human hepatic cell line. During MCLR-induced cell transformation, the expression of lncGCLC and GCLC decreased continuously, accompanied with a consistently high expression of miR-122-5p. Knockdown of lncGCLC promoted cell proliferation, migration and invasion, but reduced cell apoptosis. A xenograft nude mouse model demonstrated that knockdown of lncGCLC promoted tumor growth. Furthermore, knockdown of lncGCLC significantly upregulated miR-122-5p expression, suppressed GCLC expression and GSH levels, and enhanced oxidative DNA damages. More importantly, the expression of lncGCLC in human HCC tissues was significantly downregulated in the high-microcystin exposure group, and positively associated with GCLC level in HCC tissues. Together, these findings suggest that lncGCLC plays an anti-oncogenic role in MCLR-induced malignant transformation by regulating GCLC expression.

The Glu69Asp Polymorphism of EME1 Gene is Associated with an Increased Risk of Hepatocellular Carcinoma in Guangxi Population, China.

Background: The dysfunction of Essential meiotic endonuclease 1 homolog 1 (EME1) can lead to genomic instability and tumorigenesis. Single nucleotide polymorphisms (SNPs) in the EME1 gene have been reported to be associated with the risk of several cancers, but its association with hepatocellular carcinoma (HCC) has not been investigated. This study aimed to determine the association between EME1 SNPs and the risk of HCC. Methods: This study included 645 HCC patients and 649 healthy controls from a Guangxi population of Southern China, and genotyped three functional SNPs (Glu69Asp: rs3760413A>C, Ile350Thr: rs12450550T>C, and rs11868055A>G) of the EME1 gene utilizing the Agena MassARRAY platform. Results: The rs3760413C variant genotypes (AC+CC: Glu/Asp+Asp/Asp) conferred a 1.419-fold risk of HCC compared to the AA (Glu/Glu) genotype (adjusted OR = 1.419, 95% CI = 1.017-1.980), and the allele C increased the risk of HCC in a dose-dependent manner (P trend = 0.017). Moreover, the effects of the rs3760413C variant genotypes were more pronounced in individuals who drank pond/ditch water (adjusted OR = 3.956, 95% CI = 1.413-11.076) than in those who never drank (P = 0.033). We further observed that a potential carcinogen microcystin-LR induced more DNA oxidative damages in peripheral blood mononuclear cells from the carriers of rs3760413C variant genotypes than those from the subjects with AA genotype (P = 0.006). A nomogram was also constructed combining the rs3760413A>C polymorphism and environmental risk factors for predicting HCC risk with a good discriminatory ability (concordance index = 0.892, 95% CI: 0.874-0.911) and good calibration (mean absolute error = 0.005). Conclusion: Our data suggest that the Glu69Asp missense polymorphism (rs3760413) of EME1 gene is associated with the risk of HCC, which may be a susceptible biomarker of HCC in the Guangxi population.

Genetic Variant of PP2A Subunit Gene Confers an Increased Risk of Primary Liver Cancer in Chinese.

BACKGROUND: Protein phosphatase 2A (PP2A, a serine/threonine phosphatase) is frequently inactivated in many types of cancer, including primary liver cancer (PLC). Genetic variations in PP2A subunits have been reported to be associated with the risk of many types of cancer but rarely in PLC. This study aims to assess the association between functional polymorphisms of PP2A subunit genes and the risk of PLC in Chinese. METHODS: In a case-control study with a total of 541 PLC patients and 547 controls in Guangxi province of Southern China, we genotyped six putatively functional polymorphisms (rs10421191G>A, rs11453459del>insG, rs1560092T>G, rs7840855C>T, rs1255722G>A and rs10151527A>C) of three PP2A subunit genes (PPP2R1A, PPP2R2A and PPP2R5E) using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry platform. RESULTS: The rs11453459insG variant genotypes (ins/ins+del/ins) of PPP2R1A were found to be significantly associated with an increased risk of PLC compared with the del/del genotype (adjusted OR = 1.290, 95% CI = 1.009-1.650), and the number of insert G allele worked in a dose-dependent manner (P trend= 0.007). The stratified analysis showed that the effects of rs11453459insG variant genotypes were more evident in the subgroup who drink pond-ditch water (adjusted OR = 3.051, 95% CI = 1.264-7.364) than those never drink (P = 0.041). The carriers of rs11453459 del/ins genotype had a significantly lower level of PPP2R1A mRNA expression in liver cancer tissues than those of the del/del genotype (P = 0.021). Furthermore, we used microcystin-LR, a carcinogen presents in the pond-ditch water, to treat human peripheral blood mononuclear cells and found that the cells from carriers of rs11453459insG variant genotypes induced more DNA oxidative damages than those from the del/del genotype carriers (P < 0.001). CONCLUSION: These findings suggest that the PPP2R1A rs11453459del>insG polymorphism is associated with an increased risk of PLC, especially for persons with a history of drinking pond-ditch water. This insertion/deletion polymorphism may be a susceptible biomarker for PLC in Chinese.