Elevated TMCO1 expression in gastric cancer is associated poor prognosis and promotes malignant phenotypes of tumor cells by inhibiting apoptosis

doi:10.12122/j.issn.1673-4254.2025.11.11

Abstract

Abstract:

Objective To investigate the impact of high expression of transmembrane and coiled helix structural domain 1 (TMCO1) on prognosis of gastric cancer and the possible mechanisms. Methods TMCO1 expression in gastric cancer and its effect on gastric cancer progression and prognosis were analyzed using publicly available databases and clinical data of patients undergoing radical surgery in our hospital, and its possible biological functions were explored using KEGG and GO analyses. In gastric cancer HGC-27 cells, the effects of lentivirus-mediated TMCO1 overexpression and TMCO1 silencing on cell apoptosis, proliferation, invasion and migration were examined. Results TMCO1 expression was significantly elevated in gastric cancer tissues (P<0.05), and its high expression was positively correlated with cancer progression (P<0.001) and a lowered postoperative 5-year survival rate of the patients (P<0.05). Bioinformatic analyses suggested that TMCO1 may affect gastric cancer cell apoptosis via Wnt signaling. In HGC-27 cells, TMCO1 overexpression significantly promoted tumor cell proliferation, inhibited cell apoptosis, and enhanced cell migration and invasion, whereas TMCO1 silencing produced the opposite effects. Western blotting showed that β-catenin levels were significantly upregulated in TMCO1-overexpressing cells and downregulated in cells with TMCO1 silencing. Conclusion TMCO1 is overexpressed in gastric cancer tissues, and its high expression promotes gastric cancer progression and affects long-term prognosis of the patients possibly by activating the Wnt/ β-catenin signaling pathway to inhibit apoptosis of gastric cancer cells.

Key words: gastric cancer, transmembrane and coiled-coil domain 1, apoptosis, prognosis, Wnt/β-catenin

Bowen SONG, Renjie ZHOU, Ying XU, Jinran SHI, Zhizhi ZHANG, Jing LI, Zhijun GENG, Xue SONG, Lian WANG, Yueyue WANG, Lugen ZUO. Elevated TMCO1 expression in gastric cancer is associated poor prognosis and promotes malignant phenotypes of tumor cells by inhibiting apoptosis[J]. Journal of Southern Medical University, 2025, 45(11): 2385-2393.

Figures/Tables 9

Fig.1 TMCO1 expression is elevated in gastric cancer tissues in positive correlation with the expression of Ki67. A: Expression of TMCO1 in different human tumors (*P<0.05, **P<0.01, ***P<0.001 vs Normal). B: Expression levels of TMCO1 in gastric cancer (*P<0.05). C, D: Immunohistochemistry for detecting TMCO1 expression in gastric cancer tissues and adjacent tissues and the relative IOD values (*P<0.05 vs adjacent tissue). E, F: Immunohistochemistry for detecting Ki67 expression in gastric cancer and adjacent tissues and the relative IOD value (*P<0.05 vs adjacent tissue). G, H: Correlation analysis of TMCO1 and Ki67 expressions.

Fig.2 Correlation between TMCO1 expression level and progression of gastric cancer based on tumor grade (A) and stage (B). ***P<0.001 vs Normal.

Tab.1 Correlation between TMCO1 expression levels and parameters of gastric cancer progression

Factor	n	TMCO1 expression [n, (%)]		χ²	P
Factor	n	Low (n=52)	High (n=52)	χ²	P
Gender
Male	72	40 (55.6%)	32 (44.4%)	2.889	0.089
Female	32	12 (37.5%)	20 (62.5%)
Age (year)
˂60	49	28 (57.1%)	21 (42.9%)	1.891	0.169
≥60	55	24 (43.6%)	31 (56.4%)
CEA (μg/L)
˂5	40	28 (70.0%)	12 (30.0%)	10.400	0.001
≥5	64	24 (37.5%)	40 (62.5%)
CA19-9 (kU/L)
˂37	38	29 (76.3%)	9 (23.7%)	16.587	˂0.001
≥37	66	23 (34.8%)	43 (65.2%)
Tumor size (cm)
˂5	46	26 (56.5%)	20 (43.5%)	1.403	0.236
≥5	58	26 (44.8%)	32 (55.2%)
Cancer cell type
Adenocarcinoma	70	36 (51.4%)	34 (48.6%)	0.175	0.676
Other	34	16 (47.1%)	18 (52.9%)
T stage
1-2	37	24 (64.9%)	13 (35.1%)	5.076	0.024
3-4	67	28 (41.8%)	39 (58.2%)
N stage
0-1	42	27 (64.3%)	15 (35.7%)	5.751	0.016
2-3	62	25 (40.3%)	37 (59.7%)

Fig.3 High expression of TMCO1 is associated with decreased postoperative 5-year survival rate of gastric cancer patients. A: Kaplan-Meier (KM) online platform analysis. B: KM survival curves for analyzing clinical data of patients in our hospital. C: Predictive value of TMCO1 for 5-year survival after radical gastrectomy.

Tab.2 Univariate and multivariate Cox regression analysis of prognostic factors influencing 5-year survival of gastric cancer patients

Factor	Univariate analysis		Multivariate analysis
Factor	Log-rank χ²	P	HR	95% CI	P
Gender (male vs female)	0.041	0.840
Age (˂60 years vs ≥60 years)	3.189	0.074
TMCO1 expression (high vs low)	44.369	˂0.001	3.449	1.966-6.053	˂0.001
CEA (˂5 μg/L vs ≥5 μg/L)	29.662	˂0.001	2.513	1.394-4.530	0.002
CA19-9 (˂37 kU/L vs ≥37 kU/L)	33.690	˂0.001	2.934	1.593-5.405	˂0.001
Tumor size (˂5 cm vs ≥5 cm)	3.084	0.079
Cancer cell type (adenocarcinoma vs other)	1.336	0.248
T stage (T1-T2 vs T3-T4)	20.352	˂0.001	2.217	1.265-3.887	0.005
N stage (N0-N1 vs N2-N3)	26.017	˂0.001	2.202	1.218-3.981	0.009

Fig.4 KEGG and GO enrichment analysis of TMCO1. A: KEGG enrichment analysis shows that TMCO1 is related to the Wnt signaling pathway. B: GO enrichment analysis shows that TMCO1 is associated with cell apoptosis process.

Fig.5 High expression of TMCO1 inhibits apoptosis and promotes proliferation of gastric cancer cells. A, D: Validation of TMCO1 overexpression and TMCO1 silencing in HGC-27 cells. B: CCK8 assay for assessing HGC-27 cell proliferation. C, E: TMCO1 regulates the expression of proliferation-associated proteins Ki67 and PCNA in HGC-27 cells. F, G: Flow cytometry for analyzing apoptosis of HGC-27 cells. *P<0.05, ***P˂0.001, ****P˂0.0001 vs Vector group.

Fig.6 TMCO1 overexpression promotes migration and invasion of gastric cancer cells. A, C, D: Cell migration and invasion of HGC-27 cells. B, E: Wound-healing assay. *P<0.05 vs Vector group.

Fig.7 TMCO1 regulates the Wnt signaling pathway in gastric cancer cells. A: Detection of β‑catenin protein expression in HGC-27 cells with TMCO1 overexpression or silencing by Western blotting. B: Analysis of the IOD values of β‑catenin in HGC-27 cells. *P<0.05 vs Vector group.

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