Introduction: Caveolin-1 is a ˜20-kDa scaffold protein enriched in lipid rafts of the plasma membrane
that interacts with pathogens and cellular receptors. Caveolin-1 functions as a tumor
modulator in vivo by acting as a checkpoint for signaling cascades involved in cell
growth and survival. However, the role of caveolin-1 in the stomach is unknown.
Methods: Expression of caveolin in human gastric cancer was assessed by immunohistochemistry
and Western blot analyis. mRNA levels were assessed by quantitative PCR. Various functional
assays were established to identify caveolin-dependent effects in gastric cancer cell
lines.
Results: Immunohistochemistry of biopsies from gastric cancer (GC) patients (n=41) revealed
that both the non-neoplastic mucosa and intestinal metaplastic epithelium expressed
caveolin-1. However, GC cells of only three (7%) of 41 patients expressed caveolin-1
and were all of the intestinal type. Both caveolin-1 mRNA and protein levels were
decreased in 14 (74%) of 19 and 7 (54%) of 13 GC patients compared to tumor-free tissue.
Strong caveolin-1 reactivity was also found in the non-epithelial compartment (myocytes,
fibroblasts, perineurium, endothelium) of both GC and tumor-free tissue and its frequency
increased with the differentiation status of the tumor. In a series of human GC cells,
caveolin-1 expression was low in cells derived from primary GC (AGS, SNU1) but positively
correlated with the cell line's origin from distal metastases (N87, KATOIII, SNU5,
MKN45, MKN7). Ectopic caveolin-1 slowed proliferation of adherent AGS cells but enhanced
growth and survival in a soft agar matrix. Conversely, RNAi-knockdown of caveolin-1
in MKN45 accelerated cell growth independent of anchorage conditions.
Conclusions: These data indicate that loss of the growth inhibitory role of caveolin-1 in GC cells
is an early event in gastric carcinogenesis and may contribute to its pathogenesis,
while its late regain in metastatic cells may unfold its prosurvival function(s).
