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International journal of clinical and experimental pathology

Alternative splicing of NUMB, APP and VEGFA as the features of pancreatic ductal carcinoma.


PMID 26261495

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of malignancy in pancreatic carcinoma. Here we report our discovery on the correlations between transcriptional alternative splicing (AS) of NUMB, APP, VEGFA and PDAC in patients. The expression of NUMB, APP, VEGFA from patient samples was determined by qRT-PCR. AS of these genes was examined through laser induced fluorescence capillary electrophoresis. Correlation between the AS of the genes and results from clinical laboratory examinations were analyzed. Expression of NOTHC1 and NOTCH4 as downstream target genes was examined by qRT-PCR and Western blot. Quantitative results indicated that expression of NUMB was significantly lower in tumor tissues (TT) than in para-tumor tissues (TP) (P<0.05), while APP (P<0.01) and VEGFA (P<0.05) were significantly higher. AS transcript percentage of NUMB PRR(S) was lower in TT than TP (P<0.05). AS transcript percentage of VEGFA (105+185) was significantly lower in TT than TP (P<0.05) compared to higher expression of VEGFA (206+338) (P<0.05). Regression analysis indicated that AS transcript of NUMB PRR(L) correlated with tumor size (P<0.01), while AS transcripts of APP and VEGFA correlated with results of laboratory examinations. To reveal the correlation between AS and its downstream targets, NOTCH1 and NOTCH4 were selected as NUMB gene targets and detected to be significantly higher in TT than TP (P<0.05). Alternative splicing of APP, VEGFA and NUMB may play an important role in pathogenesis of pancreatic ductal adenocarcinoma. Among the 3 genes, PRR(L) form of NUMB gene is highly expressed in TT and positively correlated with tumor size, while PRR(S) is lacking in TT and negatively correlated with NOTCH expression suggesting that PRR(S) might be protective in tumorogenesis and shows NOTCH pathway down regulation ability.