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Meta-Analysis
. 2024 Jan 2;16(1):66-88.
doi: 10.18632/aging.205338. Epub 2024 Jan 2.

Overexpression of MTFR1 promotes cancer progression and drug-resistance on cisplatin and is related to the immune microenvironment in lung adenocarcinoma

Qian-Yun Li  1 , Qiang Guo  2 , Wei-Min Luo  2 , Xiang-Yu Luo  2 , Yan-Mei Ji  3 , Li-Qiang Xu  2 , Jia-Long Guo  2 , Rong-Shu Shi  1 , Feng Li  1 , Cheng-Yi Lin  2 , Jun Zhang  2 , Di Ke  1
Affiliations
Meta-Analysis

Overexpression of MTFR1 promotes cancer progression and drug-resistance on cisplatin and is related to the immune microenvironment in lung adenocarcinoma

Qian-Yun Li et al. Aging (Albany NY). .

Abstract

Objective: The roles of MTFR1 in the drug resistance of lung adenocarcinoma (LAC) to cisplatin remain unexplored. In this study, the expression, clinical values and mechanisms of MTFR1 were explored, and the relationship between MTFR1 expression and immune microenvironment was investigated in LAC using bioinformatics analysis, cell experiments, and meta-analysis.

Methods: MTFR1 expression and clinical values, and the relationship between MTFR1 expression and immunity were explored, through bioinformatics analysis. The effects of MTFR1 on the growth, migration and cisplatin sensitivity of LAC cells were identified using cell counting kit-8, wound healing and Transwell experiments. Additionally, the mechanisms of drug resistance of LAC cells involving MTFR1 were investigated using western blotting.

Results: MTFR1 was elevated in LAC tissues. MTFR1 overexpression was associated with sex, age, primary therapy outcome, smoking, T stage, unfavourable prognosis and diagnostic value and considered an independent risk factor for an unfavourable prognosis in patients with LAC. MTFR1 co-expressed genes involved in the cell cycle, oocyte meiosis, DNA replication and others. Moreover, interfering with MTFR1 expression inhibited the proliferation, migration and invasion of A549 and A549/DDP cells and promoted cell sensitivity to cisplatin, which was related to the inhibition of p-AKT, p-P38 and p-ERK protein expression. MTFR1 overexpression was associated with stromal, immune and estimate scores along with natural killer cells, pDC, iDC and others in LAC.

Conclusions: MTFR1 overexpression was related to the unfavourable prognosis, diagnostic value and immunity in LAC. MTFR1 also participated in cell growth and migration and promoted the drug resistance of LAC cells to cisplatin via the p-AKT and p-ERK/P38 signalling pathways.

Keywords: MTFR1; drug resistance; immune infiltration; lung adenocarcinoma; prognosis.

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Conflict of interest statement

CONFLICTS OF INTEREST: The authors declare no conflicts of interest related to this study.

Figures

Figure 1
Figure 1
MTFR1 expression levels in LAC tissues from the TCGA and XENA databases. (A–C) The data of TPM type; (D, E) The data of FPKM type. Abbreviations: LAC: lung adenocarcinoma; TCGA: The Cancer Genome Atlas; TPM: transcripts per million; FPKM: Fragments Per Kilobase Million; ***P < 0.001.
Figure 2
Figure 2
Diagnostic values of MTFR1 in LAC from the TCGA and XENA databases. (A, B) The data of TPM type; (C) The data of FPKM type. Abbreviations: LAC: lung adenocarcinoma; TCGA: The Cancer Genome Atlas; TPM: transcripts per million; FPKM: Fragments Per Kilobase Million.
Figure 3
Figure 3
The levels of MTFR1 have a significant difference in the clinicopathological features of patients with LAC. (A) Age; (B) Gender; (C) Smoking; (D) T stage; (E, F) Treatment effects. Abbreviation: LAC: lung adenocarcinoma; *P < 0.05; **P < 0.01; ***P < 0.001.
Figure 4
Figure 4
Prognostic values of MTFR1 in LAC from the TCGA database. (A) Overall survival; (B) DSS; (C) PFI. Abbreviations: LAC: lung adenocarcinoma; DSS: disease-free survival; PFI: progression-free interval; TCGA: The Cancer Genome Atlas.
Figure 5
Figure 5
MTFR1 over-expression was related to the overall survival time in patients with LAC using meta-analysis. Abbreviations: LAC: lung adenocarcinoma.
Figure 6
Figure 6
MTFR1-related prognosis nomograms. (A) Overall survival; (B) Progression-free interval.
Figure 7
Figure 7
Inhibition of MTFR1 expression could delay the proliferation, migration and invasion of A549 cells. (A, B) Construction of cell model with downregulated MTFR1 expression; (C) Cell proliferation; (D) Cell invasion; (E) Cell migration. *P < 0.05; ***P < 0.001.
Figure 8
Figure 8
Inhibition of MTFR1 expression could delay the progression and promote the sensitivity to cisplatin of A549/DDP cells. (A, B) Construction of cell model with downregulated MTFR1 expression; (C) Cell viability; (D) Cell proliferation; (E) Cell invasion; (F) Cell migration. *P < 0.05; **P < 0.01; ***P < 0.001.
Figure 9
Figure 9
Inhibition of MTFR1 expression could promote the sensitivity to cisplatin of LAC cells via the p-AKT and p-ERK/P38 signalling pathways. (A) mRNA expression in A549 cells; (B) mRNA expression in A549/DDP cells; (C) Protein expression in A549 and A549/DDP cells; (D) Protein expression of statistics analysis. Abbreviation: LAC: lung adenocarcinoma.
Figure 10
Figure 10
MTFR1 expression correlated with the LAC immune microenvironment. (A) Immune score; (B) Stromal score; (C) ESTIMATE score (D–F) Stromal, immune and ESTIMATE scores were statistically significant in high- and low-MTFR1 groups. Abbreviation: LAC: lung adenocarcinoma.
Figure 11
Figure 11
MTFR1 expression correlated with the LAC immune cells. (A) Natural killer cells; (B) pDCs; (C) IDC; (D) Th2 cells; (E) DCs; (F) Mast cells; (G) Eosinophils; (H)TFH; (I) Treg. Abbreviation: LAC: lung adenocarcinoma.
Figure 12
Figure 12
MTFR1 expression correlated with the LAC immune cell markers. (A) HLA-DPB1; (B) CD1C; (C) HLA-DQB1; (D) HLA-DPA1; (E) STAT5A; (F) ITGAM; (G) HLA-DRA; (H) CSF1R; (I) TGFB1. Abbreviation: LAC: lung adenocarcinoma.
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