ArticlePloS one2013
Klotho endows hepatoma cells with resistance to anoikis via VEGFR2/PAK1 activation in hepatocellular carcinoma.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 44 citations in OpenAlex.
- Anoikis: To Die or Not to Die?International journal of molecular sciences · 2026Review
- Roles of anoikis in hepatocellular carcinoma therapy and the assessment of anoikis-regulatory molecules as therapeutic targets.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- P-21 Activated Kinases in Liver Disorders.Cancers · 2023Review
- The multikinase inhibitor axitinib in the treatment of advanced hepatocellular carcinoma: the current clinical applications and the molecular mechanisms.Frontiers in immunology · 2023Review
- VEGFR2 insufficiency enhances phosphotoxicity and undermines Klotho's protection against peritubular capillary rarefaction and kidney fibrosis.American journal of physiology. Renal physiology · 2023Article
- Investigation of the Role of Induced Overexpression of the Isolated Secreted Klotho on the A-172 Human Glioblastoma Cells.Journal of molecular neuroscience : MN · 2022Article
- Clinicopathological and Prognostic Significance of Klotho and Estrogen Receptors Expression in Human Hepatocellular Carcinoma.The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology · 2021Article
- Metabolic Spectrum of Liver Failure in Type 2 Diabetes and Obesity: From NAFLD to NASH to HCC.International journal of molecular sciences · 2021Review
- Role of Fibroblast Growth Factor 23 (FGF23) and αKlotho in Cancer.Frontiers in cell and developmental biology · 2020Review
- Effect of PAK1 gene silencing on proliferation and apoptosis in hepatocellular carcinoma cell lines MHCC97-H and HepG2 and cells in xenograft tumor.Gene therapy · 2018Article
- Zerumbone suppresses the potential of growth and metastasis in hepatoma HepG2 cells via the MAPK signaling pathway.Oncology letters · 2018Article
- Concentrations of fetuin-A, osteoprotegerin and α-Klotho in patients with alcoholic liver cirrhosis.Experimental and therapeutic medicine · 2016Article
- Klotho plays a critical role in clear cell renal cell carcinoma progression and clinical outcome.The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2016Article
- BET Bromodomain Suppression Inhibits VEGF-induced Angiogenesis and Vascular Permeability by Blocking VEGFR2-mediated Activation of PAK1 and eNOS.Scientific reports · 2016Article
- Klotho: a tumor suppressor and modulator of the Wnt/β-catenin pathway in human hepatocellular carcinoma.Laboratory investigation; a journal of technical methods and pathology · 2016Review
- Sorafenib-based combined molecule targeting in treatment of hepatocellular carcinoma.World journal of gastroenterology · 2015Review
- α-Klotho Expression in Human Tissues.The Journal of clinical endocrinology and metabolism · 2015Article
- Klotho: a novel biomarker for cancer.Journal of cancer research and clinical oncology · 2015Review
- p21-activated kinase 1 determines stem-like phenotype and sunitinib resistance via NF-κB/IL-6 activation in renal cell carcinoma.Cell death & disease · 2015Article
- Clinical observation of liver cancer patients treated with axitinib and cabozantinib after failed sorafenib treatment: a case report and literature review.Cancer biology & therapy · 2015Review
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 1 country.
Funding
Abstract
Klotho was originally characterized as an aging suppressor gene that predisposed Klotho-deficient mice to premature aging-like syndrome. Although Klotho was recently reported to exhibit tumor suppressive properties during various malignant transformations, the functional role and molecular mechanism of Klotho in hepatocarcinogenesis remains poorly understood. In our present study, immunohistochemical Klotho staining levels in a clinical follow-up of 52 hepatoma patients were significantly associated with liver cirrhosis, tumor multiplicity and venous invasion. The overall survival rate of hepatoma patients with high Klotho expression was significantly lower than those patients with low Klotho expression. Moreover, Klotho overexpression increased cellular migration, anchorage-independent growth, and anoikis resistance in hepatoma cells. Klotho overexpression elevated p21-activated kinase 1 (PAK1) expression and shRNA-mediated PAK1 knockdown and kinase activity inhibition with kinase dead mutant PAK1 K299R coexpression or allosteric inhibitor IPA3 treatment reversed anoikis resistance in Klotho-overexpressed hepatoma cells. More importantly, the pivotal significance of upregulated VEGFR2 protein levels mediated by Klotho expression was confirmed by VEGFR2 inhibitor Axitinib and blocking antibody treatment in hepatoma cells. Axitinib treatment sensitized anoikis was reversed by constitutive active mutant PAK1 T423E coexpression in Klotho-overexpressed hepatoma cells. Conversely, knockdown of Klotho reduced VEGFR2/PAK1 dependent anoikis resistance, which could be reversed by PAK1 T423E. These results revealed a novel oncogenic function of Klotho in promoting anoikis resistance via activating VEGFR2/PAK1 signaling, thus facilitating tumor migration and invasion during hepatoma progression, which could provide a putative molecular mechanism for tumor metastasis.
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