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Carcinogenesis |
Sealy Center for Cancer Cell Biology [Y. G-P., N. R. M., A. P. F.], Departments of Human Biological Chemistry & Genetics [N. R. M., A. P. F.], Pharmacology [A. P. F.], and Pathology [Z. G.], University of Texas Medical Branch, Galveston, Texas 77555, and Vel-Lab Research, Houston, Texas 77054 [M. A. V.]
Protein kinase C (PKC) has been implicated in colon carcinogenesis in
humans and in rodent models. However, little is known about the
specific role of individual PKC isozymes in this process. We recently
demonstrated that elevated expression of PKC ßII in the colonic
epithelium induces hyperproliferation in vivo (N. R. Murray et al., J. Cell Biol.,
145: 699–711, 1999). Because hyperproliferation is a
major risk factor for colon cancer, we assessed whether specific
alterations in PKC ßII expression occur during azoxymethane-induced
colon carcinogenesis in mice. An increase in PKC ßII expression was
observed in preneoplastic lesions (aberrant crypt foci, 3.7-fold)
compared with saline-treated animals, and in colon tumors
(7.8-fold; P = 0.011) compared with
uninvolved colonic epithelium. In contrast, PKC 
and PKC ßI (a
splicing variant of PKC ßII) expression was slightly decreased in
aberrant crypt foci and dramatically reduced in colon tumors.
Quantitative reverse transcription-PCR analysis revealed that PKC mRNA
levels do not directly correlate with PKC protein levels, indicating
that PKC isozyme expression is likely regulated at the
posttranscriptional/translational level. Finally, transgenic mice
expressing elevated PKC ßII in the colonic epithelium exhibit a trend
toward increased colon tumor formation after exposure to azoxymethane.
Taken together, our results demonstrate that elevated expression of PKC
ßII is an important early, promotive event that plays a role in colon
cancer development.
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