Potential diagnostic of lymph node metastasis and prognostic values of TM4SFs in papillary thyroid carcinoma patients

Abstract

Background: Although the prognosis of papillary thyroid carcinoma (PTC) is relatively good, it causes around 41,000 deaths per year, which is likely related to recurrence and metastasis. Lymph node metastasis (LNM) is an important indicator of PTC recurrence and transmembrane 4 superfamily (TM4SF) proteins regulate metastasis by modulating cell adhesion, migration, tissue differentiation, and tumor invasion. However, the diagnostic and prognostic values of TM4SF in PTC remain unclear.Methods: This study aimed to identify TM4SF genes with predictive value for LNM and prognostic value in PTC using bioinformatic analysis. We screened the differentially expressed genes (DEGs) of the TM4SF family in PTC using data from TCGA, constructed a PPI network using STRING, and evaluated the predictive role of TM4SF1 in LNM via a binary logistic regression analysis and ROC curve. We assessed the association between TM4SF1 expression and DNA methylation, and determined the functional and mechanistic role of TM4SF1 in promoting LNM via GSEA, KEGG, and GO. We estimated the relationship between each TM4SF gene and overall survival (OS, estimated by Kaplan-Meier analysis) in patients with PTC and established a predictive model of prognostic indicators using a LASSO penalized Cox analysis to identify hub genes. Finally, we explored the correlation between TM4SFs and TMB/MSI.Results: We identified 21 DEGs from the 41 TM4SFs between N0 (without LNM) and N1 (with LNM) patients, with TM4SF1, TM4SF4, UPK1B, and CD151 being highly expressed in the N1 group; several DEGs were observed in the TNM, T, and N cancer stages. The “integrins and other cell-surface receptors” pathway was the most significantly enriched functional category related to LNM and TM4SFs. TM4SF1 was identified as an indicator of LNM (AUC= 0.702). High levels of TM4SF1 might be related to Wnt/β-catenin pathway and epithelial–mesenchymal transition (EMT) process in PTC. The higher expression of TM4SF1 was also related to DNA promoter hypomethylation. CD9, TM4SF4, TSPAN2, and TSPAN16 were associated with OS in PTC patients and TSPAN2 has great potential to become a prognostic marker of PTC progression. For the prognostic model, the riskscore = (-0.0058)*CD82+(-0.4994)*+(0.1584)*TSPAN11+(1.7597)*TSPAN19+(0.2694)*TSPAN2 (lambda.min = 0.0149). The AUCs for 3-year, 5-year, and 10-year OS were 0.81, 0.851, and 0.804. TSPAN18, TSPAN31, and TSPAN32 were associated with both TMB and MSI in PTC patients.Conclusion: Our findings identified TM4SF1 as a potential diagnostic marker of LNM and TSPAN2 as a prognostic factor for patients with PTC. Our study provides a novel strategy to assess prognosis and predict effective treatments in PTC.

Integrated multi-omics analyses reveal the TM4SF family genes with prognostic and therapeutic relevance in hepatocellular carcinoma

“…Numerous studies have reported that TM4SF family members play a crucial role in many kinds of cancer [22][23][24]. However, their biological roles and prognostic value in LIHC have rarely been characterized.…”

Validating linalool as a potential drug for breast cancer treatment based on machine learning and molecular docking

“…TM4SF4 (transmembrane 4 superfamily 4) is a transmembrane protein that is regarded as a regulator of pancreas development (Anderson et al, 2011). TM4SF4 is associated with the prognosis of colorectal cancer (Huang et al, 2012), lung cancer (Choi et al, 2017), thyroid cancer (Wang et al, 2022) and liver cancer (Tang et al, 2024). Previous studies have shown that TM4SF4 is only highly expressed in a few cases of BC patients, however knocking down TM4SF4 can inhibit the growth of BC cells (Jung et al, 2021).…”

Identification of novel gene signature predicting lymph node metastasis in papillary thyroid cancer via bioinformatics analysis and in vitro validation

“…Identi cation of speci c biomarkers related to PTC metastasis had been highly feasible due to high-throughput sequencing and bioinformatics technology development and several studies have screened gene signatures predicting the LNM of PTC. Kun Wang et al systematically evaluated the expression and potential mechanisms of transmembrane 4 superfamily (TM4SF) and revealed that a ve-gene prognostic model involved in TM4SFs could assess PTC progression effectively (Wang et al 2022). Yang Yu et al established a three hub-gene model including PTGS, MET and ICAM1 from immunerelated genes (IRGs) by LASSO and Random Forest method and validated those signature immune genes had potential functions for lymphatic metastasis in papillary thyroid cancer (Yu et al 2023) .…”