Related Experiment Videos

Reduced expression of RAS protein activator like-1 in gastric cancer

Motoko Seto1, Miki Ohta, Tsuneo Ikenoue

  • 1Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. seto@kanto-ctr-hsp.com

International Journal of Cancer
|May 18, 2010
PubMed

Insights

Reduced RASAL1 expression, often due to genetic and epigenetic changes, contributes to gastric cancer. Restoring RASAL1 may inhibit tumor growth, highlighting RAS signaling

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • RAS signaling pathway deregulation is common in human cancers.
  • RAS mutations are infrequent in gastric cancer, suggesting alternative activation mechanisms.
  • RASAL1 (RAS protein activator like-1) normally inhibits RAS activity and its decreased expression was linked to colon tumor progression.

Purpose of the Study:

  • To investigate the role of decreased RASAL1 expression in gastric cancer development.
  • To explore the mechanisms causing RASAL1 silencing in gastric tumors.

Main Methods:

  • Immunoblotting to assess RASAL1 expression in gastric cancer cell lines.
  • Gene knockdown and forced expression experiments to evaluate RASAL1's effect on cell proliferation and signaling.
  • Immunohistochemistry on primary gastric tumors to analyze RASAL1 expression levels.
  • Analysis of RASAL1 promoter methylation and loss of heterozygosity (LOH) in cell lines and tumors.
  • Treatment with histone deacetylase inhibitors to assess potential restoration of RASAL1 expression.

Main Results:

  • RASAL1 expression was reduced in a significant proportion of gastric cancer cell lines and primary tumors.
  • RASAL1 knockdown enhanced mitogen-activated protein kinase signaling, while its forced expression reduced cell proliferation.
  • RASAL1 silencing in cell lines and tumors was associated with promoter methylation and/or LOH.
  • Histone deacetylase inhibitor treatment partially restored RASAL1 expression in some cell lines.

Conclusions:

  • Reduced RASAL1 expression, driven by genetic (LOH) and epigenetic (methylation) alterations, contributes to gastric carcinogenesis.
  • The findings underscore the importance of the RAS signaling pathway in gastric cancer.
  • RASAL1 represents a potential therapeutic target in gastric cancer treatment.

Related Concept Videos

The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
The Retinoblastoma Gene01:20

The Retinoblastoma Gene

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...