HIF1A

HIF1A (Hypoxia-Inducible Factor 1 alpha / HIF-1α)

一行要約

低酸素環境下で安定化される hypoxia master transcription factor であり、ARNT (HIF-1β) と二量体を形成して HRE (hypoxia response element) を介し VEGF / GLUT1 / LDHA / PDK1 等 100+ 標的遺伝子の発現を駆動する。Warburg-like 解糖系シフト、血管新生 (angiogenesis)、erythropoiesis、metastasis、treatment resistance、neutrophil-driven NETosis を統合する hub TF として、がん生物学で最も中心的な代謝・低酸素応答因子の一つ。2019 年 Nobel 医学賞 (Semenza・Kaelin・Ratcliffe) で機能が認証された。

主要エビデンス

Hypoxia master TF: 低酸素下で HIF-1α の prolyl-hydroxylation (PHD2) が抑制され、von Hippel-Lindau (VHL) E3 ligase による ubiquitin-proteasome 分解が止まり蓄積。ARNT と heterodimer 形成 → HRE motif (5’-RCGTG-3’) 結合で VEGF・GLUT1・LDHA・PDK1・CA9 等を induce。Semenza らの 1990s の一連の研究 (Cell 1992, PNAS 1995) で確立。

腫瘍生物学での中心性: 固形腫瘍内部の低酸素領域で HIF-1α は (1) angiogenesis (VEGF 上昇)、(2) Warburg effect / aerobic glycolysis、(3) EMT・stemness、(4) immune evasion (PD-L1 induction の一部寄与)、(5) chemoresistance / radioresistance、(6) metastasis を駆動する。Hanahan の Hallmarks 2.0 / 2022 update で reprogramming energy metabolism / inducing angiogenesis / activating invasion-metastasis の 3 hallmark を結ぶ central node として描かれる。

HIF1A と好中球生物学: hypoxic neutrophil で HIF-1α が NETosis を促進する経路が報告されており (Mahdy ら、Ai ら)、低酸素 TME での NET 形成・転移カスケードへの寄与が注目される。

HIF-2α 選択的阻害剤の臨床応用: VHL 病・clear cell RCC で belzutifan (HIF-2α-selective) が FDA 承認 (2021)。HIF-1α 選択的阻害剤の臨床応用は開発初期段階。

メカニズム

Oxygen sensing cascade:

1. 通常酸素下 — PHD2 (prolyl hydroxylase domain) が HIF-1α の Pro402/Pro564 を hydroxylation
2. VHL E3 ligase が hydroxylated HIF-1α を認識し ubiquitination → proteasome 分解 (半減期数分)
3. 低酸素下 — PHD 活性低下 → HIF-1α 安定化 → 核移行 → ARNT と heterodimer 形成
4. CBP/p300 を recruit して HRE 結合遺伝子の transcription を駆動

HIF-1α vs HIF-2α:

• HIF-1α: acute hypoxia 応答、解糖系シフト、widespread tissue distribution
• HIF-2α (EPAS1): chronic hypoxia 応答、erythropoietin 産生、kidney / endothelium 限局
• がん種ごとに dominant isoform が異なる (RCC: HIF-2α / glioblastoma: HIF-1α stem cells / 多くの carcinoma: HIF-1α)

関連エンティティ・概念

• Pathway: HIF-1 signaling pathway / VEGF-VEGFR pathway / Warburg-glycolysis pathway
• Related TF / partner: HIF-2α (EPAS1) / ARNT (HIF-1β) / VHL / PHD2 (EGLN1)
• Drugs: Belzutifan (HIF-2α 選択的、RCC 承認)
• Concept: Tumor-promoting-inflammation / Avoiding-immune-destruction / Neutrophil-extracellular-traps (hypoxia-driven NETosis 経路)
• MOC: cancer-biology / cancer-neutrophils / lung-cancer-biology

関連論文

直近 30 件のみ表示中 (関連 49 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

Basic-Brain metastasis

• Bergers et al. NatRevCancer 2021 — The metabolism of cancer cells during metastasis
• Rabas et al. NatRevCancer 2024 — Cancer-induced systemic pre-conditioning of distant organs building a niche for metastatic cells

Basic-Extracellular vesicles

• Qiu et al. MolCancerRes 2025 — Insulin resistance increases TNBC aggressiveness and brain metastasis via adipocyte-derived exosomes
• Dixson et al. NatRevMolCellBiol 2023 — Context-specific regulation of extracellular vesicle biogenesis and cargo selection
• Bertolini et al. Oncogene 2022 — NFkappaB activation by hypoxic small extracellular vesicles drives oncogenic reprogramming in a breast cancer
• Sleeboom et al. SciTranslMed 2024 — The extracellular matrix as hallmark of cancer and metastasis From biomechanics to therapeutic targets

Basic-Immunotherapy

• Galassi et al. CancerCell 2024 — The hallmarks of cancer immune evasion
• Wang et al. Cell 2026 — CLIM-TIME identifies metastatic microenvironment modulators for T cell therapy response
• Elahi et al. NatRevImmunol 2026 — Immune regulation by erythroid cells how erythroid progenitor cells and mature red blood cells shape immunity

Basic-Liquid-biopsy

• Ring et al. NatRevCancer 2023 — Biology, vulnerabilities and clinical applications of circulating tumour cells

Basic-Neutrophil and myeloid cell

• Wu et al. Cell 2024 — Neutrophil profiling illuminates anti-tumor antigen-presenting potency
• Chen et al. FrontImmunol 2022 — Roles of the exosomes derived from myeloid-derived suppressor cells in tumor immunity and cancer progression
• Aegerter et al. Immunity 2022 — Biology of lung macrophages in health and disease
• Chang et al. NatBiomedEng 2026 — CAR-neutrophils produced in vivo to treat glioma
• Wan et al. NatCellBiol 2026 — Thy1+ cancer stem cells drive metastasis through a pseudohypoxic state shaped by neutrophil-derived mitochondria
• Lasser et al. NatRevClinOncol 2024 — Myeloid-derived suppressor cells in cancer and cancer therapy
• Veglia et al. NatRevImmunol 2021 — Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity
• Ng et al. Science 2024 — Deterministic reprogramming of neutrophils within tumors
• Horvath et al. TrendsCancer 2024 — Beyond binary bridging neutrophil diversity to new therapeutic approaches in NSCLC

Basic-Oncogene and genetics

• Ning et al. CancerChemotherPharmacol 2023 — The role of alternative splicing in lung cancer
• Sui et al. CellDeathDiscov 2025 — Lactylation in cancer metabolic mechanism and therapeutic strategies
• Wong-Rolle et al. JImmunotherCancer 2022 — Spatial meta-transcriptomics reveal associations of intratumor bacteria burden with lung cancer cells showing a

Basic-Others

• Tang et al. CancerCell 2026 — Mapping cell type-resolved transcriptomic profiles to patient survival in pancreatic cancer
• Li et al. Cell 2026 — Cellular architecture and neighborhood-informed virtual spatial tumor profiling from histopathology
• Goswami et al. NatCancer 2023 — Myeloid-specific KDM6B inhibition sensitizes glioblastoma to PD1 blockade
• Sikkema et al. NatMed 2023 — An integrated cell atlas of the lung in health and disease
• Kang et al. NatRevClinOncol 2026 — Translating ferroptosis into oncology challenges, opportunities and future directions

Basic-Tumor microenvironment

• Subudhi et al. Cell 2026 — Targeting angiogenesis lessons from 25 years of normalizing tumor vasculature
• Karimi et al. Nature 2023 — Single-cell spatial immune landscapes of primary and metastatic brain tumours
• Sorin et al. Nature 2023 — Single-cell spatial landscapes of the lung tumour immune microenvironment