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Medicineworld.org: How cancer-causing bacterium works?

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How cancer-causing bacterium works?




Scientists have discovered a mechanism by which Helicobacter pylori, the only known cancer-causing bacterium, disables a tumor suppressor protein in host cells.

The newly released study, in the journal Oncogene, reports the discovery of a previously unknown mechanism linking H. pylori infection and stomach cancer, the second leading cause of cancer deaths worldwide.

About two-thirds of the world's population is infected with H. pylori, a bacterium that can survive in the harsh environment of the stomach. Most infected people never develop disease. For a significant minority, however, infection with H. pylori leads to inflammation, ulcers and in some cases, stomach (gastric) cancer.



How cancer-causing bacterium works?
A protein produced by some strains of H. pylori interacts with a host tumor suppressor protein. This leads to degradation of the tumor suppressor protein, researchers found.

Credit: Yutaka Tsutsumi, M.D. Professor Department of Pathology Fujita Health University School of Medicine

H. pylori's ability to cause disease is closely linked to a virulence protein called CagA. Prior studies have observed that CagA-positive strains are much more likely to cause inflammation and spur the abnormal cell division and growth of cells that lead to cancer.

H. pylori injects CagA into the epithelial cells that line the stomach. Within the cells, CagA is able to hijack various signaling pathways and disrupt proper cellular functions.

Other studies have identified RUNX3 (pronounced RUNKS-three) as an important gastric cancer tumor suppressor.

Loss of expression of RUNX3 is causally linked to the development of gastric cancer, said University of Illinois medical biochemistry professor Lin-Feng Chen, who led the study. RUNX3 guards against tumor formation by spurring the production of factors that target unhealthy cells for destruction.

"Eventhough emerging evidence suggests that RUNX3 is a tumor suppressor whose inactivation is involved in the initiation and progression of gastric cancer," the authors wrote, "the trigger for RUNX3 inactivation within gastric cells is largely unknown."

"The protein, RUNX3, is a transcription factor, so it activates different kinds of genes controlling cell growth and death," Chen said. "The first thing we wanted to see was whether H. pylori has any effect on the transcription activity of RUNX3".

Two graduate students in Chen's lab, Ying-Hung Nicole Tsang and Acacia Lamb, began the study by examining RUNX3 transcription activity in H. pylori-infected gastric epithelial cells. They observed that infection with CagA-positive H. pylori inhibited the transcription activity of RUNX3 and reduced levels of the RUNX3 protein in cells.

CagA-negative H. pylori had no effect on RUNX3 levels or activity.

"In fact, CagA alone is sufficient to down-regulate the RUNX3 transcription activity and reduce the expression of RUNX3, further supporting the importance of this bacterial protein in the genesis of gastric disease," Chen said.

Further tests revealed that CagA and RUNX3 physically interact with each other in human epithelial cells. The scientists observed that a newly identified domain within CagA, the WW domain, recognizes a sequence in the RUNX3 protein known as the "PY motif." They further showed that this interaction leads to the "tagging" of RUNX3 for degradation via a process called ubiquitination.

Prior studies observed that there are several unique sequences within the.

carboxyl-terminal region of CagA that are vital to the protein's ability to interact with host proteins and disrupt normal cellular processes.

"This is the first time anybody has identified a unique domain within the.

amino-terminal region of the CagA protein, and it will help us to better understand how this oncogenic protein functions," Chen said. "This study has uncovered a new step in the initiation of H. pylori-induced gastric cancer".

The accumulation of a number of deleterious changes in cells leads to the development of cancer. RUNX3 helps cells react when cellular processes go awry, so H. pylori-induced degradation of RUNX3 "could produce conditions in which aberrant cellular changes are less inhibited," Chen said.

Chen's group is working to identify the molecular mechanism by which CagA targets RUNX3 for degradation. He and colleagues hope to design small molecules that can specifically inhibit the interaction between RUNX3 and CagA and block the degradation of RUNX3. Such drugs appears to be used to prevent the gastric diseases induced by H. pylori


Posted by: Janet    Source




Did you know?
Scientists have discovered a mechanism by which Helicobacter pylori, the only known cancer-causing bacterium, disables a tumor suppressor protein in host cells. The newly released study, in the journal Oncogene, reports the discovery of a previously unknown mechanism linking H. pylori infection and stomach cancer, the second leading cause of cancer deaths worldwide.

Medicineworld.org: How cancer-causing bacterium works?

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