MAR 25, 2015 08:15 AM PDT

Protein Could Account for Rise in Colon Cancer

Colon cancer is one of the leading causes of cancer-related deaths worldwide. In spite of research into the genetic mutations that are responsible for colon cancer, its numbers have increased from 500,000 deaths in 1990 to 700,000 in 2010.

With the help of grants from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, a team of researchers from the University of Pennsylvania has discovered a protein called MSI2 and reported the results in Nature Communications. MSI2 could be a new target for therapeutic intervention in colorectal cancer, help to explain the complexities the initiation and progression of the disease and even clarify how the disease can return after lying dormant for years.

Authors included: Christopher Lengner, an assistant professor in the Department of Animal Biology in Penn's School of Veterinary Medicine, senior author; Penn Vet collaborators Shan Wang, Ning Li, Maryam Yousefi, Angela Nakauka-Ddamba and Kimberly Parada; other Penn researches Fan Li, Brian Gregory and Shilpa Rao; Gerard Minuesa and Michael G. Kharas from Memorial Sloan-Kettering Cancer Center; Zhengquan Yu from China Agricultural University; and Yarden Katz from the Broad Institute. Lengner has been focusing his research on stem cell potency, the way in which stem cells can differentiate into a variety of cell types. Some cancer researchers believe that a population of so-called cancer stem cells can sustain cancer in the body once it is established, just as normal stem cells renew and sustain healthy cells.

Lengner and Kharas previously determined that an RNA binding protein called MSI2 played a role in supporting the potency of hematopoietic stem cells. They found that the same protein was highly active in blood cancers. Unlike other genes that result in increased tumor formation when mutated, MSI2 itself is not directly mutated in tumors, but the normal, intact gene is highly activated as cancer mutates. MSI2 promotes cancer by altering the ability of RNA to make proteins. Because traditional research techniques usually identify mutations in DNA sequence and alterations in gene expression patterns, they did not detect the role of MSI2.

In the new research, the team looked for RNA transcripts highly expressed in cancerous tissues but not in normal tissue. They determined that overexpression of MSI2 was a common characteristic of colon cancer tumors. When they examined mice bred to lack APC, a key protein associated with a very high risk of colon cancer when lost, they discovered that these animals had high levels of MSI2 expression. Using colorectal cancer cell lines to block MSI2 activity, they found the growth of the tumors to be strongly inhibited, a clue that MSI2 promotes cancer growth. When they bred mice to induce overexpression of MSI2 in the intestine, they saw that the mice looked very similar to animals in which APC had been lost. Mouse cells lost their ability to differentiate and died within three or four days.

As Lengner explained, "The dogma for the past 15 years has been that colorectal cancer is initiated by the loss of APC that triggers activation of ?-catenin, in turn driving uncontrolled stem cell division. But there's been some evidence recently that suggests that, while ?-catenin is a critical oncogene downstream of APC loss, it isn't the only way losing APC leads to tumor formation. Based on our results, we think that activation of MSI2 downstream of APC loss drives this metabolic activation of stem cells and blocks stem cell differentiation."
About the Author
  • Ilene Schneider is the owner of Schneider the Writer, a firm that provides communications for health care, high technology and service enterprises. Her specialties include public relations, media relations, advertising, journalistic writing, editing, grant writing and corporate creativity consulting services. Prior to starting her own business in 1985, Ilene was editor of the Cleveland edition of TV Guide, associate editor of School Product News (Penton Publishing) and senior public relations representative at Beckman Instruments, Inc. She was profiled in a book, How to Open and Operate a Home-Based Writing Business and listed in Who's Who of American Women, Who's Who in Advertising and Who's Who in Media and Communications. She was the recipient of the Women in Communications, Inc. Clarion Award in advertising. A graduate of the University of Pennsylvania, Ilene and her family have lived in Irvine, California, since 1978.
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