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

Abstract

Background: General Transcription Factor II-I Repeat Domain-Containing Protein 1 (GTF2IRD1) is a member of the GTF21 gene family, which encodes a set of multifunctional transcription factors. However, the potential function of GTF2IRD1 in pancreatic cancer (PC) still remains unknown. Study on GTF2IRD1 might provide a new insight into the carcinogenesis and therapeutics of PC.

Methods: In the current study, the clinical significance and potential biological of GTF2IRD1 were evaluated by bioinformatics analysis. The oncogenic role of GTF2IRD1 in PC was also determined using in vitro studies. Possible associations between GTF2IRD1 expression and tumor immunity were analyzed using ESTIMATE algorithm and single-sample Gene Set Enrichment Analysis (ssGSEA).

Results: GTF2IRD1 expression was significantly up-regulated in tumor tissues, and positively associated with higher histologic grade, higher American Joint Committee on Cancer (AJCC) stage, and worse prognosis. Function enrichment analysis demonstrated that GTF2IRD1 may be involved in pancreatic adenocarcinoma pathway, TGF-β signaling pathway, and tumor-infiltrating lymphocyte (TIL) related biological functions, such as T-cell receptor signaling pathway, leukocyte transendothelial migration, resistin as a regulator of inflammation, and regulation of leukocyte-mediated cytotoxicity. Knockdown of GTF2IRD1 expression inhibited cancer cell proliferation, colony formation, and invasion in vitro. ESTIMATE algorithm and ssGSEA demonstrated that GTF2IRD1 expression negatively correlated with the infiltration and anti-tumor activity of TILs, especially for CD8+ T cells.

Conclusion: The study demonstrates that GTF2IRD1 overexpression promotes tumor progression and correlates with less CD8+ T cells infiltration in PC.

Keywords: CD8+ T cells; GTF2IRD1; T cell receptor signaling pathway; TGF-β; pancreatic cancer.

Figure 1. GTF2IRD1 overexpression predicts worse prognosis in PC

(A–D) Multiple databases demonstrated that GTF2IRD1 was overexpressed in PC. (E–G) KM survival analysis revealed that patients with higher expression of GTF2IRD1 had a shorter OS than those with lower expression of GTF2IRD1 (*P-value <0.05; **P-value <0.01; ****P-value <0.0001).

Figure 2. Correlation analysis between GTF2IRD1 expression and function enrichment analysis

Figure 3. GTF2IRD1 knockdown suppresses the proliferation and invasion of PC cells lines

(A) RT-PCR analysis validated the knockdown of GTF2IRD1 in PANC-1 and AsPC-1 cells transfected with negative control siRNA (NC) or si-GTF2IRD1. (B) Assessment of cell proliferation using the MTT assay. (C) Colony formation assay was used to determine the colony-formation ability of PANC-1 and AsPC-1 cells transfected with si-GTF2IRD1. (D) Transwell assay was performed to determine the invasive capacity of PANC-1 and AsPC-1 cells transfected with si-GTF2IRD1 (**P-value < 0.01; ****P-value < 0.0001).

Figure 4. Correlation analysis of GTF2IRD1 expression and CD8⁺ T-cells infiltration in PC using the TIMER web tool