Overexpression of Transcription Intermediary Factor 1 γ (TIF1γ) Is an Early Event in Colorectal Carcinogenesis and Inversely Related to Smad4 Inactivation in Colorectal Carcinoma
S Jain, M Yu, S Singhal, F Francis, C Hajdu, S Suriawinata, M Zhang, N Aladhamy, L Chiriboga, R Pan, P Lee, J Wang, R Xu. New York University School of Medicine, New York, NY; Brooklyn Hospital Center, Brooklyn, NY; Dartmouth-Hitchcock Medical Center, Lebanon, NH; NYU School of Medicine, New York, NY
Background: TIF1γ is a cofactor or competitor of Smad4 on TGFβ pathway. Prior studies have shown that Smad4 deletion occurs in 30-50% of colorectal cancer and there is inverse relationship between the expression of Smad4 and TIF1γ in vitro. It is unknown whether TIF1γ has an opposite effect compared to Smad4 in colorectal carcinogenesis and about its significance of overexpression in colorectal neoplasms.
Design: Tissue microarrays were prepared from paraffin-embedded tissue, including 51 colorectal carcinoma (CRC), 25 tubular adenoma (TA), 12 hyperplastic polyps (HP) with matched normal epithelium (NE). Immunohistochemistry was performed using antibodies against TIF1γ, Smad4 and TGFβII to characterize their expression patterns in CRC, TA, HP and NE. The expression levels were scored semi-quantitatively: 0 negative, 1+ weak, 2+ moderate and 3+ strong expression. Statistical analyses were performed with student t-test and Fisher exact test.
Results: Overexpression of TIF1γ is more frequently found in neoplasms, 15/25 (60%) TA and 24/51 (47%) CRC compared to 3/12 (25%) HP (p<0.05), but there is no statistical difference between TA and CRC. Inactivation of SMAD4 is seen in 22/51 (43%) CRC, but none in TA and HP. Overexpression of TGFβII is also more commonly seen in neoplasms, 13/25 (52%) TA and 29/51(57%) CRC compared to 3/12 (25%) HP(P<0.05); however, no statistical difference is found between CRC and TA. Furthermore, there is a correlation between TIF1γ overexpression and Smad4 inactivation as well as between Smad4 inactivation and TGFβII overexpression (p<0.05), but no correlation between TIF1γ and TGFβII overexpression. There is no statistical difference in TIF1γ and TGFβII overexpression or Smad4 inactivation between paired primary CRC and metastasis and between CRCs with and without metastasis.
Conclusions: Overexpression of TIF1γ occurs in early stage of colorectal carcinogenesis, and shows an inverse relationship with Smad4 inactivation. The findings suggest that TIF1γ may have a role independent from, as well as a collaborative effect with Smad4 in colorectal carcinogenesis.
Tuesday, March 23, 2010 1:00 PM
Poster Session IV # 77, Tuesday Afternoon