Dataset Information

Comprehensive Analysis of IGFBPs as Biomarkers in Gastric Cancer

ABSTRACT:

Objective

Gastric cancer is the fifth most common cancer worldwide and the third leading cause of cancer-related deaths. Insulin-like growth-factor-binding proteins (IGFBPs) were initially identified as passive inhibitors that combined with insulin-like growth factors (IGFs) in serum. However, more recent data have shown that they have different expression patterns and a variety of functions in the development and occurrence of cancers. Thus, their various roles in cancer still need to be elucidated. This study aimed to explore the IGFBPs and their prognostic value as markers in gastric cancer.

Methods

Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan–Meier Plotter, cBioPortal, GeneMANIA, and TIMER were used to analyze the differential expression, prognostic value, genetic alteration, and association with immune cell infiltration of IGFPBs in gastric cancer.

Results

Expression levels of IGFBP3, IGFBP4, and IGFBP7 were significantly elevated in gastric cancer tissues, whereas those of IGFBP1 were reduced in normal tissues. IGFBP1/5/7 expression was significantly associated with overall survival whereas IGFBP6/7 expression was significantly correlated with disease-free survival in gastric cancer patients. IGFBP3/5/6/7 were associated with clinical cancer stage. Gene ontology and Kyoto Encyclopedia of Genes and Genome analyses showed that IGFBP3/5/7 were mainly enriched in focal adhesion, extracellular matrix structural constituent, cell-substratist junction, extracellular structure, and matrix organization. Stomach adenocarcinoma (STAD) and gastric cancer had more IGFBP1–7 mutations than other tumor types. Hub gene analysis showed that TP53 and IGF2 expression was significantly elevated in STAD patients; PLG, PAPPA, AFP, and CYR61 were associated with overall survival rate; and IGFALS, PLG, IGF1, AHSG, and FN1 were associated with disease-free survival. Finally, IGFBP3–7 were all associated with cancer-associated fibroblast infiltration in STAD, colon adenocarcinoma, and rectal adenocarcinoma.

Conclusion

Our study provides a comprehensive analysis and selection of IGFBPs as prognostic biomarkers in STAD. This was the first bioinformatic analysis study to describe the involvement of IGFBPs, especially IGFBP7, in gastric cancer development through the extracellular matrix.

SUBMITTER: Liu Q

PROVIDER: S-EPMC8567138 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Gastric cancer (GC) is one of the most common and poor prognosis malignancy in the world. The Family with sequence similarity 83 (FAM83) comprises of eight members of A-H. Accumulating evidence confirmed important roles for FAM83 family in tumorigenesis and progression. However, the prognostic values of FAM83 family in GC still have not been clarified. Methods: ONCOMINE, UALCAN, GEPIA, THE HUMAN PROTEIN ATLAS, Kaplan-Meier Plotter, cBioPortal, DAVID, STRING and TIMER databases and R software were adopted in this study. Results: In this study, we demonstrated that the mRNA levels of FAM83 B/C/D/H were significantly up-regulated in stomach adenocarcinoma (STAD), but the protein level of FAM83G/H were remarkable lowly in STAD. Next, FAM83C/D/G/H were significantly associated with tumor stages in STAD patients. Then, the mutation rate of FAM83 family members in STAD patients was 46%, and the highest mutation rate was FAM83H (23%). Furthermore, the functions of FAM83 family and their 259 co-expression genes were primarily related to Shigellosis, RNA degradation and Ribosome biogenesis in eukaryotes pathway. Besides, we have established the prognostic model of FAM83 family in STAD, including the prognostic model of STAD patients (FAM83C/D/G), STAD with lymph node metastasis (FAM83C/D/G/H) and STAD with ERBB2 high expression (FAM83G/H). FAM83C/D high expression with a poor prognosis, while FAM83G/H high expression with a favorable prognosis of STAD. Additionally, we found that the expression of FAM83C/D/G/H were significantly correlated with the infiltration of six types of immune cells [B cells, CD8+T cells, CD4+T cells, macrophages and Myeloid dendritic cells (DC)], whereas CD4+T cells and Macrophage cells have higher risk scores (HR > 1) when FAM83C lowly expression and FAM83D highly expression. The risk score of NK cells was significantly reduced when FAM83G lowly expression and FAM83H highly expression (HR < 1). Conclusion: These findings suggested that FAM83C/D/G/H might play key roles in STAD tumorigenesis and progression, and FAM83C/D might be risk factors but FAM83G/H might be favorable prognostic factors for STAD patients. In addition, CD4+T cells and Macrophage cells may be the promoters of FAM83D in progression of STAD, while NK cells may promote the protective effect of FAM83H on STAD patients.