KIAA1199 Correlates With Tumor Microenvironment and Immune Infiltration in Lung Adenocarcinoma as a Potential Prognostic Biomarker

Abstract

Background: KIAA1199 has been considered a key regulator of carcinogenesis. However, the relationship between KIAA1199 and immune infiltrates, as well as its prognostic value in lung adenocarcinoma (LUAD) remains unclear. Methods: The expression of KIAA1199 and its influence on tumor prognosis were analyzed using a series of databases, comprising TIMER, GEPIA, UALCAN, LCE, Prognoscan and Kaplan-Meier Plotter. Further, immunohistochemistry (IHC), western blot (WB) and receiver operating characteristic (ROC) curve analyses were performed to verify our findings. The cBioPortal was used to investigate the genomic alterations of KIAA1199. Prediction of candidate microRNA (miRNAs) and transcription factor (TF) targeting KIAA1199, as well as GO and KEGG analyses, were performed based on LinkedOmics. TIMER and TISIDB databases were used to explore the relationship between KIAA1199 and tumor immune infiltration. Results: High expression of KIAA1199 was identified in LUAD and Lung squamous cell carcinoma (LUSC) patients. High expression of KIAA1199 indicated a worse prognosis in LUAD patients. The results of IHC and WB analyses showed that the expression level of KIAA1199 in tumor tissues was higher than that in adjacent tissues. GO and KEGG analyses indicated KIAA1199 was mainly involved in extracellular matrix (ECM)-receptor interaction and extracellular matrix structure constituent. KIAA1199 was positively correlated with infiltrating levels of CD4⁺ T cells, macrophages, neutrophil cells, dendritic cells, and showed positive relationship with immune marker subsets expression of a variety of immunosuppressive cells. Conclusion: High expression of KIAA1199 predicts a poor prognosis of LUAD patients. KIAA1199 might exert its carcinogenic role in the tumor microenvironment via participating in the extracellular matrix formation and regulating the infiltration of immune cells in LUAD. The results indicate that KIAA1199 might be a novel biomarker for evaluating prognosis and immune cell infiltration in LUAD.

Keywords: KIAA1199; biomarker; immune infiltration; lung adenocarcinoma; prognosis.

FIGURE 1

The expression level of KIAA1199 in different cancers. (A) The KIAA1199 expression level in various cancer tissues and their corresponding normal tissues were analyzed using the TIMER database. (B,C) The comparisons of RNA-seq expression levels in LUAD tissue (n = 483), LUSC tissue (n = 486) and normal control tissue (n = 59 for LUAD and n = 50 for LUSC). (D,E) The meta-analysis result of KIAA1199 mRNA expression in LUAD and LUSC based on LCE database. *p < 0.05; **p < 0.01; ***p < 0.001.

FIGURE 2

The correlations among the expression level of KIAA1199 and cancer stages and nodal metastasis status in LUAD and LUSC in UALCAN database. Expression levels of KIAA1199 in (A) LUAD and (B) LUSC based on different cancer stages. Expression levels of KIAA1199 in (C) LUAD and (D) LUSC based on individual cancer stages nodal metastasis status. *p < 0.05; **p < 0.01; ***p < 0.001.

FIGURE 3

The prognostic role assessment of KIAA1199 for LUAD and LUSC based on Prognoscan and Kaplan-Meier plotter database. Survival curves of (A,B) OS (overall survival) in LUAD cohort (Jacob-00182-MSK, n = 104; GSE13213, n = 117). (C) RFS (relapse-free survival) in LUAD cohort (GSE31210, n = 204). (D,E) OS in LUSC cohort (GSE4573, n = 129; GSE17710, n = 56). (F) RFS in LUSC cohort (GSE17710, n = 56). (G–I) OS, FP (first progression) and PPS (post-progression survival) in LUAD patients (n = 672; n = 443; n = 115). (J–L) OS, FP and PPS in LUSC patients (n = 271; n = 271; n = 20).

FIGURE 4

Validation for the prognostic role of KIAA1199 in LUAD and LUSC by the LCE database. The forest plot presented the results of survival meta-analyses of (A) LUAD patients. (B) LUSC patients. TE, estimate of treatment effect; seTE, standard error of treatment estimate; HR, hazard ratio; CI, confidence interval.

FIGURE 5

Experimental verification of the KIAA1199 expression in LUAD. (A) The representative immunohistochemical (IHC) images of KIAA1199 in LUAD clinical samples and their adjacent normal lung tissue (n = 72). (B) The staining intensity of KIAA1199. (C) The staining intensity of KIAA1199 for LUAD patients with or without metastasis. (D,E) The KIAA1199 protein expression level in 12 pairs of LUAD tumor tissues and adjacent normal lung tissues (T, tumor tissues; N, adjacent normal lung tissues) was displayed by bar chart. (F) Receiver operating characteristic (ROC) curve of KIAA1199 expression in 72 pairs of LUAD tumor tissues and adjacent normal lung tissues. Magnification ×200. *p < 0.05; **p < 0.01; ***p < 0.001.

FIGURE 6

Mutation status view of KIAA1199 in LUAD. (A) OncoPrint of genomic alterations in KIAA1199 across a sample set. (B,C) Mutation sites of KIAA1199 in LUAD. (D) Genetic alteration frequency of KIAA1199 in LUAD studies.

FIGURE 7

KIAA1199 co-expression genes in LUAD were identified using LinkedOmics database. (A) The Volcano Plot showed genes highly correlated with KIAA1199 in LUAD. Heat maps showed top 50 genes (B) positively and (C) negatively associated with KIAA1199 in LUAD, respectively.

FIGURE 8

The enriched GO annotations and KEGG pathways analysis of KIAA1199 in LUAD from the LinkedOmics database. (A) GO biological process. (B) GO molecular function. (C) GO cellular components. (D) KEGG pathway. Dark blue and orange indicate FDR ≤0.05, light blue and orange indicate FDR >0.05.

FIGURE 9

Association between KIAA1199 and the immune cells infiltration in LUAD based on the TIMER analysis. (A) The correlation between the KIAA1199 expression level and tumor purity, and the recruitments of macrophages, neutrophils, dendritic cells, CD4 + T cells, CD8 + T cells, and B cells in LUAD tissues. (B) The association of KIAA1199 copy number variation (CNV) with the B cells, CD8 + T cells, CD4 + T cells, macrophages, neutrophils, and dendritic cells in LUAD. *p < 0.05; **p < 0.01; ***p < 0.001.

FIGURE 10

The correlations among KIAA1199 and tumor-infiltrating lymphocytes (TILs), chemokines and chemokine receptors in TISIDB database. Correlation of KIAA1199 expression with (A,B) 28 types of TILs; (C,D) chemokines; (E,F) chemokine receptors in LUAD.