Overexpression of LIMA1 Indicates Poor Prognosis and Promotes Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma

Abstract

Background: LIMA1 encodes LIM domain and actin binding 1, a cytoskeleton-associated protein whose loss has been linked to migration and invasion behavior of cancer cells. However, the roles of LIMA1 underlying the malignant behavior of tumors in head and neck squamous cell carcinoma (HNSC) are not fully understood. Methods: We conducted a multi-omics study on the role of LIMA1 in HNSC based on The Cancer Genome Atlas data. Subsequent in vitro experiments were performed to validate the results of bioinformatic analysis. We first identified the correlation between LIMA1 and tumor cell functional states according to single-cell sequencing data in HNSC. The potential downstream effects of LIMA1 were explored for gene ontology and Kyoto Encyclopedia of Genes and Genomes pathways through functional enrichment analysis of the gene sets that correlated with LIMA1 in HNSC. The prognostic role of LIMA1 was assessed using the log rank test to compare difference in survival between LIMA1High and LIMA1Low patients. Univariate Cox regression and multivariate Cox regression were further carried out to identify the prognostic value of LIMA1 in HNSC. Results: LIMA1 was identified as a prognostic biomarker and is associated with epithelial-mesenchymal transition (EMT) progress in HNSC. In vitro silencing of LIMA1 suppressed EMT and related pathways in HNSC. Conclusions: LIMA1 promotes EMT and further leads to tumor invasion and metastasis. Increased expression of LIMA1 indicates poor survival, identifying it as a prognostic biomarker in HNSC.

Characterization of LIMA1 and its emerging roles and potential therapeutic prospects in cancers

“…Similarly, LIMA1 depletion was found to promote EMT and induced actin cytoskeleton remodeling in breast cancers (43) and epithelial ovarian cancers (44) significantly enhancing the migration and invasion of epithelial cancer cells both in vivo and in vitro. And another study found that the expression of LIMA1 was upregulated in head and neck tumors, driving invasion and metastasis by activating tumor-associated pathways such as PI3K-AKT and JAK-STAT signaling pathways to promote the EMT process (45). It is considered likely that DNA demethylation of the LIMA1 promoter region results in different expression levels of LIMA1 in HNSC.…”

“…Recent studies have shown that the LIMA1 gene exhibits frequent downregulation and loss in cancers (Figure 3), and it can be involved in the development of malignancy through various mechanisms (13) (Figure 4). LIMA1 is associated with the progression and metastasis of various solid tumors including oral cancer (8), esophageal cancer (79), gastric cancer (80), prostate cancer (11, 41, 42, 81), breast cancer (43), ovarian cancer (44), and head and neck squamous cell carcinoma (45,46), as well as osteosarcoma (82) and lymphoma (83, 84) (Table 2). Moreover, LIMA1 particularly plays a crucial role in biological processes such as tumor proliferation, apoptosis, migration, invasion, drug resistance, immune response (79,80).…”

“…Notably, another study has identified LIMA1 overexpression in the head and neck squamous cell carcinoma (HNSC) (45). High expression of LIMA1 is associated with carcinogenesis and predicts a poor prognosis, especially in HPV-negative and TP53-mutated HNSC.…”

“…High expression of LIMA1 is associated with carcinogenesis and predicts a poor prognosis, especially in HPV-negative and TP53-mutated HNSC. HPV is involved in 25% of HNSC cases and is strongly associated with prolonged survival in HPV-positive patients (45). The increased levels of TP53 mutation may lead to dysfunction of this gene, which has been shown to have oncogenic effects in several cancer types (101).…”

“…The increased levels of TP53 mutation may lead to dysfunction of this gene, which has been shown to have oncogenic effects in several cancer types (101). It has been reported that TP53-induced LIMA1 inhibits cell invasion and that TP53 mutations lead to upregulation of LIMA1 expression levels, leading to EMT and further driving tumor invasion and metastasis (33,45). DNA demethylation of the LIMA1 promoter region may affect its expression upregulation, positively correlating with tumor metastasis, angiogenesis, and EMT.…”