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Increased hyaluronan levels in HABP1/p32/gC1qR overexpressing HepG2 cells inhibit autophagic vacuolation regulating tumor potency.

Abstract
Tumor growth and development is influenced by its microenvironment. A major extracellular matrix molecule involved in cancer progression is hyaluronan (HA). Hyaluronan and expression of a number of hyaladherin family proteins are dramatically increased in many cancer malignancies. One such hyaladherin, hyaluronan-binding protein 1 (HABP1/p32/gC1qR) has been considered to be a biomarker for tumor progression. Interestingly, overexpression of HABP1 in fibroblast has been shown to increase autophagy via generation of excess reactive oxygen species (ROS) and depletion of HA leading to apoptosis. Cancerous cells are often found to exhibit decreased rate of proteolysis/autophagy in comparison to their normal counterparts. To determine if HABP1 levels alter tumorigenicity of cancerous cells, HepR21, the stable transfectant overexpressing HABP1 in HepG2 cell line was derived. HepR21 has been shown to have increased proliferation rate than HepG2, intracellular HA cable formation and enhanced tumor potency without any significant alteration of intracellular ROS. In this paper we have observed that HepR21 cells containing higher endogenous HA levels, have downregulated expression of the autophagic marker, MAP-LC3, consistent with unaltered levels of endogenous ROS. In fact, HepR21 cells seem to have significant resistance to exogenous ROS stimuli and glutathione depletion. HepR21 cells were also found to be more resilient to nutrient starvation in comparison to its parent cell line. Decline in intracellular HA levels and HA cables in HepR21 cells upon treatment with HAS inhibitor (4-MU), induced a surge in ROS levels leading to increased expression of MAP-LC3 and tumor suppressors Beclin 1 and PTEN. This suggests the importance of HABP1 induced HA cable formation in enhancing tumor potency by maintaining the oxidant levels and subsequent autophagic vacuolation.
AuthorsParamita Saha, Ilora Ghosh, Kasturi Datta
JournalPloS one (PLoS One) Vol. 9 Issue 7 Pg. e103208 ( 2014) ISSN: 1932-6203 [Electronic] United States
PMID25061661 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • C1QBP protein, human
  • Carrier Proteins
  • Membrane Proteins
  • Mitochondrial Proteins
  • Reactive Oxygen Species
  • Hyaluronic Acid
  • PTEN Phosphohydrolase
  • PTEN protein, human
Topics
  • Apoptosis (genetics)
  • Apoptosis Regulatory Proteins (biosynthesis)
  • Autophagy (genetics)
  • Beclin-1
  • Carrier Proteins (biosynthesis, genetics)
  • Cell Proliferation (genetics)
  • Gene Expression Regulation, Neoplastic
  • Hep G2 Cells
  • Humans
  • Hyaluronic Acid (genetics, metabolism)
  • Membrane Proteins (biosynthesis)
  • Mitochondrial Proteins (biosynthesis, genetics)
  • Neoplasms (genetics, pathology)
  • PTEN Phosphohydrolase (biosynthesis)
  • Reactive Oxygen Species (metabolism)
  • Tumor Microenvironment (genetics)

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