Related Experiment Video

Updated: Jul 14, 2025

Bile Duct Ligation in Mice: Induction of Inflammatory Liver Injury and Fibrosis by Obstructive Cholestasis
08:56

Bile Duct Ligation in Mice: Induction of Inflammatory Liver Injury and Fibrosis by Obstructive Cholestasis

Published on: February 10, 2015

52.4K

Intrinsic cancer cell phosphoinositide 3-kinase δ regulates fibrosis and vascular development in cholangiocarcinoma

Vanessa Bou Malham1,2, Nassima Benzoubir1,2, Javier Vaquero3,4

  • 1INSERM, Unité 1193, Villejuif, France.

Liver International : Official Journal of the International Association for the Study of the Liver
|October 7, 2023
PubMed
Abstract

Insights

Phosphatidylinositol-3 kinase delta (PI3Kδ) drives cholangiocarcinoma (CCA) progression and aggressiveness. Targeting PI3Kδ offers new avenues for CCA classification and treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • Class I-phosphatidylinositol-3 kinases (PI3Ks) signaling is frequently dysregulated in human cancers.
  • The specific roles of PI3K isoforms, particularly PI3Kδ, in cancer progression are not fully understood.
  • PI3Kδ has been implicated in hepatocellular carcinoma and solid tumor progression, but its role in cholangiocarcinoma (CCA) remains unexplored.

Purpose of the Study:

  • To investigate the role of PI3Kδ in the progression and aggressiveness of cholangiocarcinoma (CCA).
  • To elucidate the underlying molecular mechanisms of PI3Kδ-mediated CCA progression.
  • To explore potential therapeutic strategies targeting PI3Kδ in CCA.

Main Methods:

  • Immunohistochemical analysis of CCA patient samples.
  • RT-qPCR and immunoblotting to assess gene and protein expression.
  • Lentiviral construction for stable PI3Kδ overexpression in CCA cells.
  • 3D cell culture and in vivo xenograft mouse models.
  • Whole transcriptome analysis and pathway analysis.

Main Results:

  • High PI3Kδ expression correlates with poorly differentiated CCA.
  • PI3Kδ overexpression increases mesenchymal and stem cell markers, promoting cell plasticity.
  • PI3Kδ enhances extracellular matrix deposition, tumor angiogenesis, and lymphangiogenesis.
  • PI3Kδ-mediated effects are dependent on TGFβ/Src/Notch signaling pathways.
  • Transcriptome analysis aids in classifying CCA based on cancer progression.

Conclusions:

  • PI3Kδ plays a critical role in the progression and aggressiveness of CCA.
  • PI3Kδ promotes CCA by modulating cell morphogenesis and stroma remodeling via TGFβ/Src/Notch signaling.
  • Targeting PI3Kδ presents a promising strategy for novel CCA classification and treatment approaches.
Keywords:
EMTextracellular-matrixstemnesstumour growthvasculature development

More Related Videos

Phospholipid Mediator Induced Transformation in Three-Dimensional Cultures08:02

Phospholipid Mediator Induced Transformation in Three-Dimensional Cultures

Published on: July 27, 2022

2.5K
Isolation and 3D Collagen Sandwich Culture of Primary Mouse Hepatocytes to Study the Role of Cytoskeleton in Bile Canalicular Formation In Vitro10:12

Isolation and 3D Collagen Sandwich Culture of Primary Mouse Hepatocytes to Study the Role of Cytoskeleton in Bile Canalicular Formation In Vitro

Published on: December 20, 2019

11.6K

Related Concept Videos

Phosphoinositides and PIPs01:42

Phosphoinositides and PIPs

Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
8.6K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.6K
IP3/DAG Signaling Pathway01:11

IP3/DAG Signaling Pathway

Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the  phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
12.1K
Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...
2.6K
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
8.9K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.3K