ArticlePloS one2016
Heat Stress-Induced PI3K/mTORC2-Dependent AKT Signaling Is a Central Mediator of Hepatocellular Carcinoma Survival to Thermal Ablation Induced Heat Stress.
Article in PloS one, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 28 citations in OpenAlex.
- Integrative genomic analysis and gene expression patterns reveal a cardio-neuroendocrine signaling network for heat adaptation in geographically diverse chickens.Poultry science · 2026Article
- Boric Acid and Hyperthermia Combination: A New Cancer Therapy in The Human Hepatocellular Carcinoma and Neuroblastoma?Biological trace element research · 2026Article
- Outcomes following microwave ablation of 669 primary and metastatic lung malignancies.European radiology · 2026Article
- Sodium alginate-based tissue-mimicking phantom with tunable optical properties for laser thermotherapy.Biomedical optics express · 2025Article
- Proteomic Analysis of Differentially Expressed Plasma Exosome Proteins in Heat-StressedAnimals : an open access journal from MDPI · 2025Article
- Fibroblast growth factors induce hepatic tumorigenesis post radiofrequency ablation.Scientific reports · 2023Article
- Severe heat stress modulated nuclear factor erythroid 2-related factor 2 and macrophage migration inhibitory factor pathway in rat liver.Journal of cell communication and signaling · 2022Article
- Recent Perspectives on the Mechanism of Recurrence After Ablation of Hepatocellular Carcinoma: A Mini-Review.Frontiers in oncology · 2022Review
- Quantitative Expression of Key Cancer Markers in the AS-30D Hepatocarcinoma Model.Frontiers in oncology · 2021Article
- Moderate hyperthermic heating encountered during thermal ablation increases tumor cell activity.International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group · 2020Article
- Thermal Ablation of Metastatic Colon Cancer to the Liver.Seminars in interventional radiology · 2019Review
- Single-Dose Neoadjuvant AKT Pathway Inhibitor Reduces Growth of Hepatocellular Carcinoma after Laser Thermal Ablation in Small-Animal Model.Radiology · 2019Article
- The PI3K and MAPK/p38 pathways control stress granule assembly in a hierarchical manner.Life science alliance · 2019Article
- Heat Stress and Thermal Ablation Induce Local Expression of Nerve Growth Factor Inducible (VGF) in Hepatocytes and Hepatocellular Carcinoma: Preclinical and Clinical Studies.Gene expression · 2018Article
- Heat stress induced, ligand-independent MET and EGFR signalling in hepatocellular carcinoma.International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group · 2018Article
- Heat Stress and Hepatic Laser Thermal Ablation Induce Hepatocellular Carcinoma Growth: Role of PI3K/mTOR/AKT Signaling.Radiology · 2018Article
- Targeting STAT3 to Suppress Systemic Pro-Oncogenic Effects from Hepatic Radiofrequency Ablation.Radiology · 2018Article
- Identification of the acclimation genes in transcriptomic responses to heat stress of White Pekin duck.Cell stress & chaperones · 2017Article
- Kras mutation is a marker of worse oncologic outcomes after percutaneous radiofrequency ablation of colorectal liver metastases.Oncotarget · 2017Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
Abstract
Thermal ablative therapies are important treatment options in the multidisciplinary care of patients with hepatocellular carcinoma (HCC), but lesions larger than 2-3 cm are plagued with high local recurrence rates and overall survival of these patients remains poor. Currently no adjuvant therapies exist to prevent local HCC recurrence in patients undergoing thermal ablation. The molecular mechanisms mediating HCC resistance to thermal ablation induced heat stress and local recurrence remain unclear. Here we demonstrate that the HCC cells with a poor prognostic hepatic stem cell subtype (Subtype HS) are more resistant to heat stress than HCC cells with a better prognostic hepatocyte subtype (Subtype HC). Moreover, sublethal heat stress rapidly induces phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dependent-protein kinase B (AKT) survival signaling in HCC cells in vitro and at the tumor ablation margin in vivo. Conversely, inhibition of PI3K/mTOR complex 2 (mTORC2)-dependent AKT phosphorylation or direct inhibition of AKT function both enhance HCC cell killing and decrease HCC cell survival to sublethal heat stress in both poor and better prognostic HCC subtypes while mTOR complex 1 (mTORC1)-inhibition has no impact. Finally, we showed that AKT isoforms 1, 2 and 3 are differentially upregulated in primary human HCCs and that overexpression of AKT correlates with worse tumor biology and pathologic features (AKT3) and prognosis (AKT1). Together these findings define a novel molecular mechanism whereby heat stress induces PI3K/mTORC2-dependent AKT survival signaling in HCC cells and provide a mechanistic rationale for adjuvant AKT inhibition in combination with thermal ablation as a strategy to enhance HCC cell killing and prevent local recurrence, particularly at the ablation margin.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.