A genomic variant of ALPK2 is associated with increased liver fibrosis risk in HIV/HCV coinfected women

McIntosh, Alec T.; Wei, Renhuizi; Ahn, Jaeil; Aouizerat, Brad; Kassaye, Seble; Augenbraun, Michael; Price, Jennifer; French, Audrey L.; Gange, Stephen J.; Anastos, Kathryn; Goldman, Radoslav

doi:10.1371/journal.pone.0247277

Cited by 4 publications

(3 citation statements)

References 42 publications

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“…A member of the alpha kinase family, alpha protein kinase 2 (ALPK2), has a largely conserved alpha protein kinase domain. Initially, a domain of ALPK2 is identified to be similar to that of the elongation factor 2 kinase and is housed at 18q21.31 [ 6 , 7 ]. ALPK2 has been considered to be a Wnt/ β -catenin signaling pathway inhibitor and a regulator for cardiac development [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Alpha Protein Kinase 2 Promotes Esophageal Cancer via Integrin Alpha 11

Ainiwaer

Zhang

Niyazi

et al. 2022

BioMed Research International

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Background. As a common disease around the world, esophageal cancer (EC) primarily includes two subclasses: esophageal adenocarcinoma and esophageal squamous cell carcinoma. Mortality has been rising over the years; hence, exploring the mechanism of EC development has become critical. Among the alpha protein kinases, alpha protein kinase 2 (ALPK2) presumably has a connection with EC, but it has never been revealed before. Methods. In this study, IHC analysis was used for ALPK2 expression quantification in ES tissues. TE-1 and Eca-109, which are both human EC cell lines, were used for in vitro analysis of cell proliferation, migration, apoptosis, and colony formation. Results. ALPK2 was found to have an abundant expression within EC tissues ( P < 0.001 ), as well as in the two selected human EC cell lines ( P < 0.05 ). The data showed that ALPK2 depletion suppressed EC cell proliferation, migration, and colony formation, meanwhile stimulating apoptosis ( P < 0.001 ). The in vivo experiments also displayed inhibitory effects caused by ALPK2 depletion on EC tumorigenesis ( P < 0.001 ). It was further validated that ALPK2 depletion made the phosphorylation of Akt and mTOR, as well as CDK6 and PIK3CA levels downregulated ( P < 0.001 ). Mechanistically, we identified integrin alpha 11 (ITGA11) as a downstream gene of ALPK2 regulating EC. More importantly, we found that ITGA11 elevation promoted cell proliferation and migration and rescued the suppression effects caused by ALPK2 depletion ( P < 0.001 ). Conclusions. ALPK2 promotes esophageal cancer via integrin its downstream gene alpha 11; ALPK2 can potentially act as a target for the treatment of EC.

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Section: Introductionmentioning

confidence: 99%

Alpha Protein Kinase 2 Promotes Esophageal Cancer via Integrin Alpha 11

Ainiwaer

Zhang

Niyazi

et al. 2022

BioMed Research International

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“…ALPK2 mapped to 18q21.32 encodes a serine/threonine kinase protein that is involved in several processes, including epicardium morphogenesis and heart development, and is a negative regulator of Wnt signaling [19]. Recent studies by McIntosh et al [41] showed that ALPK2 rs3809973 (not ALPK2 rs3809983, identified in this study) is associated with an increased risk of liver fibrosis in HIV/HCV co-infected women. This may be the initial indication linking the ALPK2 variant to the pathological liver phenotype in women.…”

Section: Discussionmentioning

confidence: 57%

Whole-Exome Sequencing (WES) Reveals Novel Sex-Specific Gene Variants in Non-Alcoholic Steatohepatitis (MASH)

Wei,

Wu,

Daoud

2024

Genes

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Non-alcoholic steatohepatitis (NASH, also known as MASH) is a severe form of non-alcoholic fatty liver disease (NAFLD, also known as MASLD). Emerging data indicate that the progression of the disease to MASH is higher in postmenopausal women and that genetic susceptibility increases the risk of MASH-related cirrhosis. This study aimed to investigate the association between genetic polymorphisms in MASH and sexual dimorphism. We applied whole-exome sequencing (WES) to identify gene variants in 8 age-adjusted matched pairs of livers from both male and female patients. Sequencing alignment, variant calling, and annotation were performed using standard methods. Polymerase chain reaction (PCR) coupled with Sanger sequencing and immunoblot analysis were used to validate specific gene variants. cBioPortal and Gene Set Enrichment Analysis (GSEA) were used for actionable target analysis. We identified 148,881 gene variants, representing 57,121 and 50,150 variants in the female and male cohorts, respectively, of which 251 were highly significant and MASH sex-specific (p < 0.0286). Polymorphisms in CAPN14, SLC37A3, BAZ1A, SRP54, MYH11, ABCC1, and RNFT1 were highly expressed in male liver samples. In female samples, Polymorphisms in RGSL1, SLC17A2, HFE, NLRC5, ACTN4, SBF1, and ALPK2 were identified. A heterozygous variant 1151G>T located on 18q21.32 for ALPK2 (rs3809983) was validated by Sanger sequencing and expressed only in female samples. Immunoblot analysis confirmed that the protein level of β-catenin in female samples was 2-fold higher than normal, whereas ALPK2 expression was 0.5-fold lower than normal. No changes in the protein levels of either ALPK2 or β-catenin were observed in male samples. Our study suggests that the perturbation of canonical Wnt/β-catenin signaling observed in postmenopausal women with MASH could be the result of polymorphisms in ALPK2.

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“…While the specifc signalling pathways governed by ALPK2 are still under intensive investigation, its participation in pathways related to cell growth, survival, and motility has been observed in various studies. For example, the variant of ALPK2 rs3809973 was associated with liver fbrosis in HIV/HCV-coinfected cases [7].…”

Section: Introductionmentioning

confidence: 99%

The Influence of Alpha Kinase 2 Expression on Prognosis in Serous Ovarian Cancer Liver Metastasis

Sun,

Zhang,

et al. 2024

Journal of Clinical Pharmacy and Therapeutics

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Background. Globally, ovarian cancer is a leading contributor to cancer-related fatalities among women, with a notable concern being the occurrence of liver metastasis as a prevalent clinical complication. This study aims to investigate the potential impact of alpha kinase 2 (ALPK2) on ovarian cancer liver metastasis (OCLM), assessing its implications for patient prognosis and tumor advancement. Our research seeks to examine the prognostic significance of ALPK2 in individuals with OCLM and unravel the consequences of ALPK2 knockdown on the proliferation and invasion of ovarian cancer cells. Methods. A retrospective analysis of 49 OCLM cases from our medical center was conducted to evaluate the prognostic significance of ALPK2 through survival analyses. Experimental investigations involved the use of shRNA to knock down ALPK2 in ovarian cancer cell lines, with subsequent scrutiny of cellular changes. Results. Survival analyses revealed that ALPK2 functions as an independent adverse prognostic factor in OCLM (HR = 3.74, 95% CI: 1.34–10.42, and P=0.012). Knockdown experiments indicated a reduction in cell proliferation and invasion capacities, potentially associated with the epithelial-mesenchymal transition process. Conclusions. ALPK2 emerges as a crucial oncogene promoting tumors in OCLM. Its knockdown exhibits significant therapeutic potential by hindering cancer progression. Further investigations could solidify the role and therapeutic possibilities of ALPK2 in the treatment of ovarian cancer, particularly in cases involving liver metastasis.

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A genomic variant of ALPK2 is associated with increased liver fibrosis risk in HIV/HCV coinfected women

Cited by 4 publications

References 42 publications

Alpha Protein Kinase 2 Promotes Esophageal Cancer via Integrin Alpha 11

Alpha Protein Kinase 2 Promotes Esophageal Cancer via Integrin Alpha 11

Whole-Exome Sequencing (WES) Reveals Novel Sex-Specific Gene Variants in Non-Alcoholic Steatohepatitis (MASH)

The Influence of Alpha Kinase 2 Expression on Prognosis in Serous Ovarian Cancer Liver Metastasis

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