Sorting nexin 1 down-regulation promotes colon tumorigenesis.
OBJECTIVE
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.


METHODS
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.
Nguyen
Lananh N
LN
Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
Holdren
Matthew S
MS
Nguyen
Anthony P
AP
Furuya
Momoko H
MH
Bianchini
Michele
M
Levy
Estrella
E
Mordoh
José
J
Liu
Annie
A
Guncay
Gabriela D
GD
Campbell
Jean S
JS
Parks
W Tony
WT
D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D058305:Sorting Nexins; D013329:Structure-Activity Relationship; D033921:Vesicular Transport Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*
D034741:RNA, Small Interfering; C513978:SNX1 protein, human; D058305:Sorting Nexins; D033921:Vesicular Transport Proteins; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3