GTF2IRD1 on chromosome 7 is a novel oncogene regulating the tumor‐suppressor gene TGFβR2 in colorectal cancer

Abstract

Chromosome 7q (Ch.7q) is clonally amplified in colorectal cancer (CRC). We aimed to identify oncogenes on Ch.7q that are overexpressed through DNA copy number amplification and determine the biological and clinical significance of these oncogenes in CRC. We identified general transcription factor 2I repeat domain-containing protein 1 (GTF2IRD1) as a potential oncogene using a CRC dataset from The Cancer Genome Atlas with a bioinformatics approach. We measured the expression of GTF2IRD1 in 98 patients with CRC using immunohistochemistry and RT-quantitative PCR (RT-qPCR). The biological effects of GTF2IRD1 expression were explored by gene set enrichment analysis (GSEA). Next, we undertook in vitro cell proliferation and cell cycle assays using siGTF2IRD1-transfected CRC cells. We further investigated the oncogenic mechanisms through which GTF2IRD1 promoted CRC progression. Finally, we assessed the clinical significance of GTF2IRD1 expression by RT-qPCR. GTF2IRD1 was overexpressed in tumor cells and liver metastatic lesions. The GSEA revealed a positive correlation between GTF2IRD1 expression and cell cycle progression-related genes. GTF2IRD1 knockdown inhibited cell proliferation and induced cell cycle arrest in Smad4-mutated CRC. GTF2IRD1 downregulated the expression of the gene encoding transforming growth factor β receptor 2 (TGFβR2), a tumor-suppressor gene in Smad4-mutated CRC. On multivariate analysis, high GTF2IRD1 expression was an independent poor prognostic factor. Clinicopathological analysis showed that GTF2IRD1 expression was positively correlated with liver metastasis. In conclusion, GTF2IRD1 promoted CRC progression by downregulating TGFβR2 and could be a prognostic biomarker on Ch.7q in CRC. GTF2IRD1 could also be a novel oncogene in CRC. K E Y W O R D Scell cycle, colorectal cancer, GTF2IRD1, oncogene, TGFβR2

GTF2IRD1 overexpression promotes tumor progression and correlates with less CD8+ T cells infiltration in pancreatic cancer

“…And previous study by Huo et al reported that GTF2IRD1 overexpression correlates with poor survival in patients with breast cancer, lung cancer, and ovarian cancer [ 11 ]. Additional study by Nambara et al also identified GTF2IRD1 as an oncogene and unfavorable prognostic factor in colorectal cancer [ 8 ]. These findings strongly suggest that GTF2IRD1 is a potential oncogene and unfavorable prognostic biomarker in human cancers, including PC.…”

“…However, early study by Hasegawa et al suggested that GTF2IRD1 represses adipose tissue fibrosis through inhibiting TGF-β signaling pathway [ 24 ]. Besides, Nambara et al reported that GTF2IRD1 overexpression might result in inhibition of TGF-β signaling pathway in colorectal cancer [ 8 ]. These results suggest the tissue specificity of GTF2IRD1 in regulating TGF-β signaling pathway.…”

“…General Transcription Factor II-I Repeat Domain-Containing Protein 1 (GTF2IRD1) located at 7q11.23, is a member of the GTF21 gene family, which encodes a set of multifunctional transcription factors [ 8 ]. Early studies on GTF2IRD1 mainly focused on its association with Williams–Beuren syndrome, which is a genetic disorder associated with multiple systemic abnormalities, including hypertension, diabetes, osteoporosis, and anxiety [ 9 , 10 ].…”

“…Early studies on GTF2IRD1 mainly focused on its association with Williams–Beuren syndrome, which is a genetic disorder associated with multiple systemic abnormalities, including hypertension, diabetes, osteoporosis, and anxiety [ 9 , 10 ]. Previous oncology studies about GTF2IRD1 have been conducted in only three cancers, including colorectal cancer, breast cancer, and retinoblastoma [ 8 , 11 ]. Nevertheless, the precise function and mechanism of GTF2IRD1 in PC has not been studied to date.…”

The novel driver gene ASAP2 is a potential druggable target in pancreatic cancer

“…16 Based on insight from previous findings and our multiregional genomic analysis, we have identified novel oncogenes, including elF5-mimic protein 1 (5MP1), DEAD-Box Helicase 56 (DDX56), and general transcription factor 2I repeat domain-containing protein 1 (GTF2IRD1), located on amplified chromosome 7 in CRC. [17][18][19] Therefore, we focused on genes that were overexpressed due to gene amplification as potential therapeutic targets in PDAC, because these genes can be targeted with gene-specific medicines, including neutralizing antibodies or small chemicals.…”