The rs599839 A>G Variant Disentangles Cardiovascular Risk and Hepatocellular Carcinoma in NAFLD Patients

Background and Aims: Dyslipidemia and cardiovascular diseases (CAD) are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from steatosis to hepatocellular carcinoma (HCC). The rs599839 A>G variant, in the CELSR2-PSRC1-SORT1 cluster, has been associated CAD, but its impact on metabolic traits and liver damage in NAFLD has not been investigated yet. Methods: We evaluated the effect of the rs599839 variant in 1426 NAFLD patients (Overall cohort) of whom 131 have HCC (NAFLD-HCC), in 500,000 individuals from the UK Biobank Cohort (UKBBC) and in 366 HCC samples from The Cancer Genome Atlas (TCGA). Hepatic PSRC1, SORT1 and CELSR2 expressions were evaluated by RNAseq (n=125). Results: The rs599839 variant was associated with reduced circulating LDL, carotid intima-media thickness, carotid plaques and hypertension (p<0.05) in NAFLD patients and with protection against dyslipidemia in UKBBC. The G allele was associated with higher risk of HCC and advanced tumor stage (p<0.05) in the Overall cohort. Hepatic PSRC1, SORT1 and CELSR2 expressions were increased in NAFLD patients carrying the rs599839 variant (p<0.0001). SORT1 mRNA levels negatively correlated with circulating lipids and with those of genes involved in lipoprotein turnover (p<0.0001). Conversely, PSRC1 expression was positively related to that of genes implicated in cell proliferation (p<0.0001). In TCGA, PSRC1 over-expression promoted more aggressive HCC development (p<0.05). Conclusions: In sum, the rs599839 A>G variant improves dyslipidemia thus protecting against CAD in NAFLD patients, but as one it might promote HCC development by modulating SORT1 and PSRC1 expressions which impact on lipid metabolism and cell proliferation, respectively

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The rs599839 A>G Variant Disentangles Cardiovascular Risk and Hepatocellular Carcinoma in NAFLD Patients

Cancers ◽

10.3390/cancers13081783 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1783

Author(s):

Marica Meroni ◽

Miriam Longo ◽

Erika Paolini ◽

Anna Alisi ◽

Luca Miele ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Intima Media Thickness ◽

Carotid Intima Media Thickness ◽

Tumor Stage ◽

The Cancer Genome Atlas ◽

Advanced Tumor Stage ◽

Mrna Levels ◽

Nonalcoholic Fatty Liver ◽

Advanced Tumor

Background and Aims: Dyslipidemia and cardiovascular diseases (CVD) are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from steatosis to hepatocellular carcinoma (HCC). The rs599839 A>G variant, in the CELSR2-PSRC1-SORT1 gene cluster, has been associated CVD, but its impact on metabolic traits and on the severity liver damage in NAFLD has not been investigated yet. Methods: We evaluated the effect of the rs599839 variant in 1426 NAFLD patients (Overall cohort) of whom 131 had HCC (NAFLD-HCC), in 500,000 individuals from the UK Biobank Cohort (UKBBC), and in 366 HCC samples from The Cancer Genome Atlas (TCGA). Hepatic PSRC1, SORT1 and CELSR2 expressions were evaluated by RNAseq (n = 125). Results: The rs599839 variant was associated with reduced circulating LDL, carotid intima-media thickness, carotid plaques and hypertension (p < 0.05) in NAFLD patients and with protection against dyslipidemia in UKBBC. The minor G allele was associated with higher risk of HCC, independently of fibrosis severity (odds ratio (OR): 5.62; 95% c.i. 1.77–17.84, p = 0.003), poor prognosis and advanced tumor stage (p < 0.05) in the overall cohort. Hepatic PSRC1, SORT1 and CELSR2 expressions were increased in NAFLD patients carrying the rs599839 variant (p < 0.0001). SORT1 mRNA levels negatively correlated with circulating lipids and with those of genes involved in lipoprotein turnover (p < 0.0001). Conversely, PSRC1 expression was positively related to that of genes implicated in cell proliferation (p < 0.0001). In TCGA, PSRC1 over-expression promoted more aggressive HCC development (p < 0.05). Conclusions: In sum, the rs599839 A>G variant is associated with protection against dyslipidemia and CVD in NAFLD patients, but as one it might promote HCC development by modulating SORT1 and PSRC1 expressions which impact on lipid metabolism and cell proliferation, respectively.

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Type III TGF-β Receptor Down-Regulation Promoted Tumor Progression via Complement Component C5a Induction in Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13071503 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1503

Author(s):

Oscar Wai Ho Yeung ◽

Xiang Qi ◽

Li Pang ◽

Hui Liu ◽

Kevin Tak Pan Ng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Progression ◽

Tumor Stage ◽

Complement Component ◽

Soluble Form ◽

Advanced Tumor Stage ◽

Down Regulation ◽

Type Iii ◽

Advanced Tumor ◽

Β Receptor

Background and Aims—Transforming growth factor-beta (TGF-β) signaling orchestrates tumorigenesis and one of the family members, TGF-β receptor type III (TGFβR3), are distinctively under-expressed in numerous malignancies. Currently, the clinical impact of TGFβR3 down-regulation and the underlying mechanism remains unclear in hepatocellular carcinoma (HCC). Here, we aimed to identify the tumor-promoting roles of decreased TGFβR3 expression in HCC progression. Materials and Methods—For clinical analysis, plasma and liver specimens were collected from 100 HCC patients who underwent curative resection for the quantification of TGFβR3 by q-PCR and ELISA. To study the tumor-promoting mechanism of TGFβR3 downregulation, HCC mouse models and TGFβR3 knockout cell lines were applied. Results—Significant downregulation of TGFβR3 and its soluble form (sTGFβR3) were found in HCC tissues and plasma compared to healthy individuals (p < 0.01). Patients with <9.4 ng/mL sTGFβR3 exhibited advanced tumor stage, higher recurrence rate and shorter disease-free survival (p < 0.05). The tumor-suppressive function of sTGFβR3 was further revealed in an orthotopic mouse HCC model, resulting in 2-fold tumor volume reduction. In TGFβR3 knockout hepatocyte and HCC cells, increased complement component C5a was observed and strongly correlated with shorter survival and advanced tumor stage (p < 0.01). Interestingly, C5a activated the tumor-promoting Th-17 response in tumor associated macrophages. Conclusion—TGFβR3 suppressed tumor progression, and decreased expression resulted in poor prognosis in HCC patients through upregulation of tumor-promoting complement C5a.

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Elevated expression of ASF1B correlates with poor prognosis in human lung adenocarcinoma

Personalized Medicine ◽

10.2217/pme-2020-0112 ◽

2021 ◽

Vol 18 (2) ◽

pp. 115-127

Author(s):

Zhenxing Feng ◽

Jiao Zhang ◽

Yafang Zheng ◽

Qingzhang Wang ◽

Xiaochuan Min ◽

...

Keyword(s):

Overall Survival ◽

Lung Adenocarcinoma ◽

Tumor Development ◽

Tumor Stage ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Advanced Tumor Stage ◽

Aberrant Expression ◽

Free Survival ◽

Advanced Tumor

Aim: ASF1 is involved in tumorigenesis. However, its possible role in lung adenocarcinoma (LUAD) is unclear. This study thus explored the role of ASF1A and ASF1B in LUAD. Materials & methods: Data from The Cancer Genome Atlas and Gene Expression Omnibus were employed to investigate ASF1A and ASF1B expression and its roles in LUAD prognosis. Immunohistochemistry was applied to determine the protein expression of ASF1B of 30 LUAD patients. Results: The upregulation of ASF1B in tumor tissues is associated with worse overall survival and progress-free survival and is correlated with advanced tumor stage and tumor development. However, aberrant expression of ASF1A was not found in LUAD and ASF1A was not related to patients’ overall survival and progress-free survival. Conclusion: ASF1B could be a promising prognostic and therapeutic biomarker in LUAD.

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Mo1507 Cirrhosis Is Associated With More Advanced Tumor Stage, Decreased Treatment Eligibility, and Lower Survival in Hepatitis B Virus (HBV)-Related Hepatocellular Carcinoma (HCC): Results of a Multicenter International Cohort Study

Gastroenterology ◽

10.1016/s0016-5085(16)33829-x ◽

2016 ◽

Vol 150 (4) ◽

pp. S1134-S1135

Author(s):

Vincent L. Chen ◽

Mijung Jun ◽

An K. Le ◽

Peggy Tsai ◽

Nathan G. Kim ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cohort Study ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Tumor Stage ◽

Advanced Tumor Stage ◽

Lower Survival ◽

Advanced Tumor ◽

B Virus

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Liprin-β1 is upregulated in human hepatocellular carcinoma and is associated with advanced tumor stage

Archives of Biological Sciences ◽

10.2298/abs190116029l ◽

2019 ◽

Vol 71 (3) ◽

pp. 469-474

Author(s):

Xinying Li ◽

Jingmei Li ◽

Jiao Yang

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Stage ◽

Tumor Stage ◽

Human Hepatocellular Carcinoma ◽

Advanced Tumor Stage ◽

Advanced Clinical Stage ◽

Advanced Tumor ◽

Elevated Expression ◽

Clinicopathological Significance ◽

Liver Tissues

Liprin-?1 is one of the broadly-expressed liprin family members. Dysregulation of liprin-?1 has been implicated in several types of human cancers. However, the expression of liprin-?1 and its clinicopathological significance in human hepatocellular carcinoma (HCC) remains elusive. We evaluated the protein expression of liprin-?1 in HCC and non-tumor liver tissues by immunohistochemistry, and investigated the relationship between liprin-?1 expression and the clinicopathological attributes of HCC. We found that liprin-?1 expression was significantly higher in HCC than in non-tumor liver tissues. Further analysis showed that higher levels of liprin-?1 in HCC were significantly associated with the advanced clinical stage. Interestingly, liprin-?1 was not detected in cholangiocellular carcinoma specimens. These findings suggest that an elevated expression of liprin-?1 may be involved in HCC progression, providing the rationale that upregulation of liprin-?1 may serve as a novel biomarker for human HCC.

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PDZ Binding Kinase/T-LAK Cell-Derived Protein Kinase Plays an Oncogenic Role and Promotes Immune Escape in Human Tumors

Journal of Oncology ◽

10.1155/2021/8892479 ◽

2021 ◽

Vol 2021 ◽

pp. 1-16

Author(s):

Tingting Feng ◽

Yan Zhang ◽

Sunbin Ling ◽

Chenyang Xu ◽

Yingqi Lyu ◽

...

Keyword(s):

Protein Kinase ◽

Solid Tumors ◽

Immune Cell ◽

Immune Escape ◽

Tumor Stage ◽

The Cancer Genome Atlas ◽

Advanced Tumor Stage ◽

Mitotic Kinase ◽

Lak Cell ◽

Advanced Tumor

Background. PDZ binding kinase (PBK)/T-LAK cell-derived protein kinase (TOPK) is an important mitotic kinase that promotes tumor progression in some cancers. However, the pan-cancer analysis of PBK/TOPK and its role in tumor immunity are limited. Methods. The oncogenic and immune roles of PBK in various cancers were explored using multiple databases, including Oncomine, Human Protein Atlas, ULCAN, Tumor Immune Estimation Resource 2.0, STRING, and Gene Expression Profiling Interactive Analysis 2, and data collected from The Cancer Genome Atlas and Genotype-Tissue Expression Project. Several bioinformatics tools and methods were used for quantitative analyses and panoramic descriptions, such as the DESeq2 and Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. Results. PBK was expressed at higher levels in most solid tumors than in normal tissues in multiple databases. PBK was associated with an advanced tumor stage and grade and a poor prognosis in most cases. PBK was associated with tumor immune cell infiltration in most cases and was especially positively correlated with TAMs, Tregs, MDSCs, and T cell exhaustion in KIRC, LGG, and LIHC. PBK was closely related to TMB, MSI, and immune checkpoint genes in various cancers, and patients with higher expression of PBK in KIRC, LGG, and LIHC had higher TIDE scores and lower immune responses in the predicted results. PBK was closely related to cell cycle regulation and immune-related processes in LIHC and LGG according to GO and KEGG enrichment analyses. Conclusions. PBK may play an oncogenic role in most solid tumors and promotes immune escape, especially in KIRC, LGG, and LIHC. This study suggests the potential value of PBK inhibitors combined with immunotherapy.

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Thymosin β 10 is overexpressed and associated with unfavorable prognosis in hepatocellular carcinoma

Bioscience Reports ◽

10.1042/bsr20182355 ◽

2019 ◽

Vol 39 (3) ◽

Cited By ~ 2

Author(s):

Chunrong Song ◽

Zhong Su ◽

Jing Guo

Keyword(s):

Hepatocellular Carcinoma ◽

Human Cancer ◽

Normal Liver ◽

The Cancer Genome Atlas ◽

Migration And Invasion ◽

Tumor Biomarker ◽

Advanced Tumor Stage ◽

Poor Overall Survival ◽

Tissue Samples ◽

Advanced Tumor

Abstract Thymosin β 10 (TMSB10) has been demonstrated to be overexpressed and function as an oncogene in most types of human cancer including hepatocellular carcinoma (HCC). In our study, we present more evidence about the clinical significance and biological function of TMSB10 in HCC. First, we observed levels of TMSB10 expression were obviously increased in HCC tissues compared with normal liver tissues at The Cancer Genome Atlas (TCGA) datasets. Furthermore, we confirmed that TMSB10 mRNA and protein levels were also increased in HCC tissue samples compared with normal adjacent normal liver tissue samples. In addition, we found high TMSB10 expression was remarkably associated with the advanced tumor stage, large tumor size, distant metastasis, and poor prognosis, and acted as an independent factor for predicting poor overall survival in HCC patients. Loss-of-function studies suggested silencing of TMSB10 expression dramatically reduced cell proliferation, migration, and invasion in HCC. In conclusion, TMSB10 may hold promise as a tumor biomarker for predicting prognosis and a potential target for developing a novel therapeutic strategy.

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Comprehensive Analysis of the Prognosis and Correlations With Immune Infiltration of S100 Protein Family Members in Hepatocellular Carcinoma

Frontiers in Genetics ◽

10.3389/fgene.2021.648156 ◽

2021 ◽

Vol 12 ◽

Author(s):

Susu Zheng ◽

Linxia Liu ◽

Tongchun Xue ◽

Chuyu Jing ◽

Xin Xu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Mutation Rate ◽

S100 Protein ◽

Family Members ◽

Protein Family ◽

Advanced Tumor Stage ◽

Mrna Levels ◽

Expression Levels ◽

Immune Infiltration ◽

Advanced Tumor

S100 protein family members (S100s) are commonly dysregulated in various tumors including hepatocellular carcinoma (HCC). However, the diverse expression, mutation, prognosis and associations with immune infiltration of S100s in HCC have yet to be analyzed. Herein we investigated the roles of S100s in HCC from the Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), Human Protein Atlas, Kaplan-Meier Plotter, cBioPortal and TIMER databases. Compared with para-cancer tissues, the expression levels of S100A4/S100A6/S100A10/S100A11/S100A13/S100A14/S100P were higher in HCC tissues, while the expression levels of S100A8/S100A9/S100A12 were decreased in tumor tissues. The mRNA levels of S100A2/S100A7/S100A7A/S100A8/S100A9/S100A11 were correlated with advanced tumor stage. Besides, higher mRNA expressions of S100A6/S100A10/S100A11/S100A13/S100A14/S100P were shown to have shorter overall survival (OS), while higher expression of S100A12 was associated with favorable OS. Further, the mutation rate of S100s was investigated, and the high mutation rate (53%) was associated with shorter OS. Additionally, the expressions of S100s were found to be significantly associated with various immune infiltrating cells. Hence, our results showed that S100A6/S100A10/S100A11/S10012/S100A13/S100A14/S100P may be regarded as new prognostic or therapeutic markers and S100s inhibitors may be helpful in the combination of immunotherapies.

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