ITGB1-mediated molecular landscape and cuproptosis phenotype induced the worse prognosis in diffuse gastric cancer

Xingyu Zhu; Hao Chen; Han Li; Huicheng Ren; Chunshui Ye; Kang Xu; Jin Liu; Fengying Du; Zihao Zhang; Yuan Liu; Xiaozhou Xie; Mingfei Wang; Tianrong Ma; Wei Chong; Liang Shang; Leping Li

doi:10.3389/fonc.2023.1115510

ITGB1-mediated molecular landscape and cuproptosis phenotype induced the worse prognosis in diffuse gastric cancer

Front Oncol. 2023 Mar 16:13:1115510. doi: 10.3389/fonc.2023.1115510. eCollection 2023.

Authors

Xingyu Zhu^{1

2

3

4}, Hao Chen⁵, Han Li⁶, Huicheng Ren^{1

2

3

4}, Chunshui Ye^{2

3

4}, Kang Xu^{1

2

3

4}, Jin Liu⁷, Fengying Du^{1

2

3

4}, Zihao Zhang^{2

3

4}, Yuan Liu^{2

3

4}, Xiaozhou Xie^{1

2

3

4}, Mingfei Wang^{2

3

4}, Tianrong Ma^{1

2

3

4}, Wei Chong^{1

2

3

4}, Liang Shang^{1

2

3

4}, Leping Li^{1

2

3

4}

Affiliations

¹ Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
² Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, China.
³ Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, China.
⁴ Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.
⁵ Clinical Research Center of Shandong University, Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, Shandong, China.
⁶ Department of Gastroenterological Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, China.
⁷ Research Center for Experimental Nuclear Medicine, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.

Abstract

Diffuse type gastric cancer was identified with relatively worse prognosis than other Lauren's histological classification. Integrin β1 (ITGB1) was a member of integrin family which played a markedly important role in tumorigenesis and progression. However, the influence of ITGB1 in diffuse gastric cancer (DGC) remains uncertain. Here, we leveraged the transcriptomic and proteomic data to explore the association between ITGB1 expression and clinicopathologic information and biological process in DGC. Cell phenotype experiments combined with quantitative-PCR (q-PCR) and western blotting were utilized to identify the potential molecular mechanism underling ITGB1.Transcriptomics and proteomics both revealed that the higher ITGB1 expression was significantly associated with worse prognosis in DGC, but not in intestinal GC. Genomic analysis indicated that the mutation frequency of significantly mutated genes of ARID1A and COL11A1, and mutational signatures of SBS6 and SBS15 were markedly increased in the ITGB1 low expression subgroup. The enrichment analysis revealed diverse pathways related to dysregulation of ITGB1 in DGC, especially in cell adhesion, proliferation, metabolism reprogramming, and immune regulation alterations. Elevated activities of kinase-ROCK1, PKACA/PRKACA and AKT1 were observed in the ITGB1 high-expression subgroup. The ssGSEA analysis also found that ITGB1 low-expression had a higher cuproptosis score and was negatively correlated with key regulators of cuproptosis, including FDX1, DLAT, and DLST. We further observed that the upregulated expression of mitochondrial tricarboxylic acid (TCA) cycle in the ITGB1 low-expression group. Reduced expression of ITGB1 inhibited the ability of cell proliferation and motility and also potentiated the cell sensitive to copper ionophores via western blotting assay. Overall, this study revealed that ITGB1 was a protumorigenic gene and regulated tumor metabolism and cuproptosis in DGC.

Keywords: Integrin β1; cuproptosis; diffuse gastric cancer; metabolism; molecular landscape.

Grants and funding

This work was supported by National Natural Science Foundation of China (82102702, 82103322, 82203854), Natural Science Foundation of Shandong Province of China (ZR2020QH180, ZR2021QH141), Youth Innovation Science and Technology Program of Shandong Provincial Universities (2022KJ187), China postdoctoral science foundation (2022M711970), Clinical Medical Science and Technology Innovation Project of Jinan (202225046), Key Research and Development Program of Shandong Province (No.2021CXGC011104; No.2019JZZY010104; No.2019GSF108146), Academic promotion programme of Shandong First Medical University (2019QL021), and Special Foundation for Taishan Scholars Program of Shandong Province (No.ts20190978).