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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Transl+Med
2018 ; 16
(1
): 191
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The TGF?-signaling pathway and colorectal cancer: associations between
dysregulated genes and miRNAs
#MMPMID29986714
Pellatt AJ
; Mullany LE
; Herrick JS
; Sakoda LC
; Wolff RK
; Samowitz WS
; Slattery ML
J Transl Med
2018[Jul]; 16
(1
): 191
PMID29986714
show ga
BACKGROUND: The TGF?-signaling pathway plays an important role in the
pathogenesis of colorectal cancer (CRC). Loss of function of several genes within
this pathway, such as bone morphogenetic proteins (BMPs) have been seen as key
events in CRC progression. METHODS: In this study we comprehensively evaluate
differential gene expression (RNASeq) of 81 genes in the TGF?-signaling pathway
and evaluate how dysregulated genes are associated with miRNA expression (Agilent
Human miRNA Microarray V19.0). We utilize paired carcinoma and normal tissue from
217 CRC cases. We evaluate the associations between differentially expressed
genes and miRNAs and sex, age, disease stage, and survival months. RESULTS:
Thirteen genes were significantly downregulated and 14 were significantly
upregulated after considering fold change (FC) of?>?1.50 or?0.67 and multiple
comparison adjustment. Bone morphogenetic protein genes BMP5, BMP6, and BMP2 and
growth differentiation factor GDF7 were downregulated. BMP4, BMP7, INHBA (Inhibin
beta A), TGFBR1, TGFB2, TGIF1, TGIF2, and TFDP1 were upregulated. In general,
genes with the greatest dysregulation, such as BMP5 (FC 0.17, BMP6 (FC 0.25),
BMP2 (FC 0.32), CDKN2B (FC 0.32), MYC (FC 3.70), BMP7 (FC 4.17), and INHBA (FC
9.34) showed dysregulation in the majority of the population (84.3, 77.4, 81.1,
80.2, 82.0, 51.2, and 75.1% respectively). Four genes, TGFBR2, ID4, ID1, and
PITX2, were un-associated or slightly upregulated in microsatellite-stable (MSS)
tumors while downregulated in microsatellite-unstable (MSI) tumors. Eight
dysregulated genes were associated with miRNA differential expression. E2F5 and
THBS1 were associated with one or two miRNAs; RBL1, TGFBR1, TGIF2, and INHBA were
associated with seven or more miRNAs with multiple seed-region matches.
Evaluation of the joint effects of mRNA:miRNA identified interactions that were
stronger in more advanced disease stages and varied by survival months.
CONCLUSION: These data support an interaction between miRNAs and genes in the
TGF?-signaling pathway in association with CRC risk. These interactions are
associated with unique clinical characteristics that may provide targets for
further investigations.