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Insulin receptor isoform B is downregulated in intestinal stem cells and tumors, limits colon cancer cell growth, and promotes differentiation
Author(s) -
Bortvedt Sarah,
Mah Amanda,
Van Landeghem Laurianne,
Simmons Jim,
Santoro M. Agostina,
Lund P. Kay
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.602.2
Subject(s) - biology , cancer research , progenitor cell , downregulation and upregulation , cellular differentiation , intestinal epithelium , colorectal cancer , cell growth , stem cell , microbiology and biotechnology , cancer , endocrinology , epithelium , gene , biochemistry , genetics
Insulin receptor (IR) has been little studied in intestinal epithelium, despite evidence that obesity and hyperinsulinemia promote intestinal dysfunction and cancer. In other organs, two IR splice variants mediate metabolism (IR‐B) or growth (IR‐A). This study examined IR‐A and IR‐B in intestinal stem cells (ISC), progenitors, and differentiated lineages isolated from Sox9‐EGFP reporter mice, normal tissue (N) and tumors (T) of Apc Min/+ mice, and colorectal cancer cells (CRC). Effects of IR‐B overexpression were tested in Caco2 CRC. We hypothesized that IR‐B predominates in differentiated normal lineages or differentiated CRC, limits CRC proliferation, and promotes differentiation.Results IR‐A predominates in ISC and progenitors; IR‐B predominates in differentiated lineages. IR‐B is downregulated in T vs N of Apc Min/+ mice and aggressively growing CRC. In Caco2 CRC, IR‐A and IR‐B are both expressed during exponential growth, but IR‐B and an IR‐B splicing enhancer are dramatically upregulated during spontaneous differentiation. Overexpression of IR‐B in Caco2 CRC dramatically reduced proliferation, but accelerated and enhanced expression of the differentiation marker sucrase. We conclude that maintained or upregulated IR‐B expression may be critical to differentiation of intestinal epithelial cells or CRC and protective against colon cancer growth. Grants: F31AG040943, NIH DK040247–19.