Sorting nexin 1 down-regulation promotes colon tumorigenesis.

Abstract

PURPOSE:

Colon cancer is one of the most common human malignancies, yet studies have only begun to identify the multiple mechanisms that underlie the development of this tumor. In this study, we have identified a novel mechanism, dysregulation of endocytic sorting, which promotes colon cancer development.

EXPERIMENTAL DESIGN:

Immunohistochemical and microarray analyses were done on human colon cancer tissue specimens to determine the levels of one endocytic protein, sorting nexin 1 (SNX1). SW480 cells, a human colon cancer cell line that retains a relatively high level of SNX1 expression, were used to assess the effects of down-regulating this protein by small hairpin RNA. Activation of signal transduction cascades was evaluated in these cells using Western blotting, and multiple functional assays were done.

RESULTS:

We determined by immunohistochemistry that the level of SNX1 was significantly down-regulated in 75% of human colon cancers. In corroborative studies using microarray analysis, SNX1 message was significantly decreased (log(2) ratio less than -1) for 8 of 19 colon carcinomas. Cell lines with reduced SNX1 levels showed increased proliferation, decreased apoptosis, and decreased susceptibility to anoikis. They also showed increased activation of epidermal growth factor receptor and extracellular signal-regulated kinase 1/2 in response to epidermal growth factor. This increased activation was abolished by inhibition of endocytosis.

CONCLUSIONS:

These data suggest that loss of SNX1 may play a significant role in the development and aggressiveness of human colon cancer, at least partially through the mechanism of increased signaling from endosomes. Further, these findings suggest that dysregulation of endocytic proteins may represent a new paradigm in the process of carcinogenesis.

• Authors: Lananh N Nguyen, Matthew S Holdren, Anthony P Nguyen, Momoko H Furuya, Michele Bianchini, Estrella Levy, José Mordoh, Annie Liu, Gabriela D Guncay, Jean S Campbell, W Tony Parks
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 23 Pg. 6952-9 (Dec 01 2006) ISSN: 1078-0432 [Print] United States
• PMID: 17145813 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Small Interfering
• SNX1 protein, human
• Sorting Nexins
• Vesicular Transport Proteins
• ErbB Receptors
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Apoptosis
• Cell Line, Tumor
• Cell Proliferation
• Colonic Neoplasms (genetics, metabolism, pathology)
• Disease Progression
• Down-Regulation (drug effects, genetics)
• ErbB Receptors (drug effects, metabolism)
• Gene Expression Regulation, Neoplastic (genetics)
• Humans
• Immunohistochemistry
• Mitogen-Activated Protein Kinase 1 (drug effects, metabolism)
• Mitogen-Activated Protein Kinase 3 (drug effects, metabolism)
• Oligonucleotide Array Sequence Analysis (methods)
• Phosphorylation
• RNA, Small Interfering (pharmacology)
• Signal Transduction (drug effects)
• Sorting Nexins
• Structure-Activity Relationship
• Vesicular Transport Proteins (drug effects, genetics, metabolism)