Transmembrane and coiled-coil domains 3 is a diagnostic biomarker for predicting immune checkpoint blockade efficacy in hepatocellular carcinoma

Abstract

Liver hepatocellular carcinoma (LIHC) is a malignancy with a high mortality and morbidity rate worldwide. However, the pathogenesis of LIHC has still not been thoroughly studied. Transmembrane and coiled-coil domains 3 (TMCO3) encodes a monovalent cation, a member of the proton transducer 2 (CPA2) family of transporter proteins. In the present study, TMCO3 expression and its relationship with cancer prognosis, as well as its immunological role in LIHC were studied by bioinformatic analysis. We found the significant overexpression of TMCO3 in LIHC in the TCGA, HCCDB, and GEO databases. In LIHC patients, high TMCO3 expression was related to poorer overall survival (OS) and TMCO3 had good predictive accuracy for prognosis. Moreover, TMCO3 was linked to the infiltrates of certain immune cells in LIHC. The correlation of TMCO3 with immune checkpoints was also revealed. Moreover, patients with LIHC with low TMCO3 expression showed a better response to immune checkpoint blockade (ICB) than those with LIHC with high TMCO3 expression. GO and KEGG enrichment analyses indicated that TMCO3 was probably involved in the microtubule cytoskeleton organization involved in mitosis, small GTPase mediated signal transduction, and TGF-β pathway. In conclusion, TMCO3 may be a potential biomarker for LIHC prognosis and immunotherapy.

Keywords: ICB; LIHC; TMCO3; diagnostics; immune infiltrates.

FIGURE 1

The TMCO3 expression in normal tissues and LIHC (A) The TMCO3 mRNA expression in human cancers and normal tissues. (B) The TMCO3 expression in LIHC and adjacent tissues in HCCDB database. The TMCO3 expression in LIHC and normal tissues in GEPIA (C), TCGA (D), and GEO (E) databases. *p < 0.05, ***p < 0.001, ****p < 0.0001.

FIGURE 2

The expression and location of TMCO3 protein (A) The TMCO3 protein IHC in LIHC and normal tissues from HPA database. (B) The association with TMCO3 expression and tumor stages of LIHC. (C) The immunofluorescence staining of TMCO3 and microtubules in U-2 OS, A-131, and U251 MG cell lines in HPA database. *p < 0.05, **p < 0.01, ****p < 0.0001, ns: no significant difference.

FIGURE 3

The prognostic value of TMCO3 in LIHC (A) Univariate and (B) multifactorial Cox analysis of TMCO3 and other clinical factors in LIHC (C) The nomogram and (D) Calibration curves of TMCO3, age, and pTNM-stage was established to predict 1-, 3-, and 5-years OS in LIHC patients. The association of TMCO3 with the OS (E) and DFS (F) in pan-cancer. The correlation of TMCO3 with OS (G) and DFS (H) in LIHC.

FIGURE 4

The association of TMCO3 with immune cell infiltrates (A) The association of TMCO3 with several immune-infiltrating cells in LIHC. The correlation of TMCO3 with Tregs (B), activated NK cells (C), resting myeloid dendritic cells (D), monocytes (E), gamma delta T cells (F), and macrophages (G).

FIGURE 5

The correlation of TMCO3 with the immune checkpoints and response to ICB (A,B) The immune checkpoints expression in TMCO3-low and TMCO3-high groups in LIHC. (C) The correlation between TMCO3 and immune checkpoints in LIHC. (D) The TIDE scores in TMCO3-low and TMCO3-high groups in LIHC. **p < 0.01, ***p < 0.001.

FIGURE 6

The potential role of TMCO3 in LIHC (A) PPI network of TMCO3 in LIHC. (B) The volcano plot showing the differential genes in TMCO3-high and TMCO3-low groups in LIHC. The top 50 genes that positively (C) and negatively (D) associated with TMCO3 in LIHC (E) Biological process GO analysis and KEGG pathway analysis (F) of TMCO3 in LIHC.

FIGURE 7

The enrichment analyses of differential genes. KEGG pathway analysis (A) and GO analysis (B) of the up-regulated genes. KEGG pathway analysis (C) and GO analysis (D) of the down-regulated genes.