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Signaling Regulatory Protein Found That Mediates Metastasis of Human Colorectal Cancer Cells

By BiotechDaily International staff writers
Posted on 09 Jul 2013
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The direct effect of the signaling regulatory protein km23-1 (also called DYNLRB1/mLC7-1/robl-1/Dnlc2a/DYRB1) on TGF-beta (transforming growth factor beta) defines its role in mediating the migration, invasion, and tumor growth of human colorectal carcinoma (CRC) cells.

TGF-beta acts as an antiproliferative factor in normal epithelial cells and at early stages of cancer development. However, when a cell is transformed into a cancer cell, parts of the TGF-beta signaling pathway are mutated, and TGF-beta no longer controls the cell. These cancer cells and surrounding stromal cells (fibroblasts) begin to proliferate. Both types of cell increase their production of TGF-beta. This TGF-beta acts on the surrounding stromal cells, immune cells, endothelial, and smooth muscle cells causing immunosuppression and angiogenesis, which makes the cancer more invasive.

Investigators at the Pennsylvania State College of Medicine (Hershey, USA) had previously described km23-1 as a novel modulator of the actin cytoskeleton that also regulated the Ras oncogene and mitogen-activated protein kinase activities in TGF-beta-sensitive epithelial cells.

In a new study, the investigators examined the functional role of this signaling regulatory protein in mediating the migration, invasion, and tumor growth of human CRC cells. Towards this end, they used small interfering RNA (siRNA) to deplete levels of km23-1 in cultures of human CRC cells.

They reported in the June 3, 2013, online edition of the journal PLOS ONE that depletion of km23-1 inhibited constitutive extracellular signal-regulated kinase (ERK) activation, as well as proinvasive ERK effector functions that included TGF-beta promoter transactivation, and TGF-beta secretion. In addition, knockdown of km23-1 reduced the paracrine effects of CRC cell-secreted factors in conditioned medium and in fibroblast co-cultures. Furthermore, km23-1 depletion in human CRC cells reduced cell migration and invasion, as well as expression of the ERK-regulated, metastasis-associated scaffold protein Ezrin. Km23-1 inhibition significantly suppressed tumor formation in an in vivo model system.

"The type of cell movement, or migration, has important implications with respect to the detection of tumor cells in the blood of cancer patients, as well as for the development of new treatments," said senior author Dr. Kathleen M. Mulder, professor of biochemistry and molecular biology at Pennsylvania State College of Medicine. "Km23-1 may be able to help in this process due to its role in the assembly of large groups of proteins favorable to cancer invasion. If we can block km23-1, we can stop the spread of colon cancer earlier, but we would also affect other important functions of the protein. In order to address this issue, we are now trying to find the specific partners of km23-1 that contribute to the invasion of the cancer cells. Then we can design more precise therapeutic agents that target critical regions of km23-1 rather than eliminating the entire protein."

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Pennsylvania State College of Medicine

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