Expression of a neuroendocrine gene signature in gastric tumor cells from CEA 424-SV40 large T antigen-transgenic mice depends on SV40 large T antigen.

A large fraction of murine tumors induced by transgenic expression
of SV40 large T antigen (SV40 TAg) exhibits a neuroendocrine
phenotype. It is unclear whether SV40 TAg induces the
neuroendocrine phenotype by preferential transformation of
progenitor cells committed to the neuroendocrine lineage or by
transcriptional activation of neuroendocrine genes. To address this
question we analyzed CEA424-SV40 TAg-transgenic mice that develop
spontaneous tumors in the antral stomach region. Immunohistology
revealed expression of the neuroendocrine marker chromogranin A in
tumor cells. By ELISA an 18-fold higher level of serotonin could be
detected in the blood of tumor-bearing mice in comparison to
nontransgenic littermates. Transcriptome analyses of antral tumors
combined with gene set enrichment analysis showed significant
enrichment of genes considered relevant for human neuroendocrine
tumor biology. This neuroendocrine gene signature was also
expressed in 424GC, a cell line derived from a CEA424-SV40 TAg
tumor, indicating that the tumor cells exhibit a similar
neuroendocrine phenotype also in vitro. Treatment of 424GC cells
with SV40 TAg-specific siRNA downregulated expression of the
neuroendocrine gene signature. SV40 TAg thus appears to directly
induce a neuroendocrine gene signature in gastric carcinomas of
CEA424-SV40 TAg-transgenic mice. This might explain the high
incidence of neuroendocrine tumors in other murine SV40 TAg tumor
models. Since the oncogenic effect of SV40 TAg is caused by
inactivation of the tumor suppressor proteins p53 and RB1 and loss
of function of these proteins is commonly observed in human
neuroendocrine tumors, a similar mechanism might cause
neuroendocrine phenotypes in human tumors.