High Expression of TIMELESS Predicts Poor Prognosis: A Potential Therapeutic Target for Skin Cutaneous Melanoma

Abstract

BackgroundSkin cutaneous melanoma (SKCM) is the most lethal skin cancer with an increasing incidence worldwide. The poor prognosis of SKCM urgently requires us to discover prognostic biomarkers for accurate therapy. As a regulator of DNA replication, TIMELESS (TIM) has been found to be highly expressed in various malignancies but rarely reported in SKCM. The objective of this study was to evaluate the relationship between TIM and SKCM tumorigenesis and prognosis.MethodsWe obtained RNA sequencing data from TCGA and GTEx to analyze TIM expression and differentially expressed genes (DEGs). Subsequently, GO/KEGG, GSEA, immune cell infiltration analysis, and protein-protein interaction (PPI) network were used to perform the functional enrichment analysis of TIM-related DEGs. Moreover, the receiver operating characteristic (ROC) curves, Cox regression analysis, Kaplan–Meier (K-M) analysis, and nomograms were applied to figure out the clinical significance of TIM in SKCM. In addition, we investigated the relationship between TIM promoter methylation and SKCM prognosis through the UALCAN database. Finally, the immunohistochemical (IHC) results of normal skin and SKCM were analyzed to determine expression differences.ResultsTIM was significantly elevated in various malignancies, including SKCM, and high expression of TIM was associated with poor prognosis. Moreover, a total of 402 DEGs were identified between the two distinct TIM expression groups, and functional annotation showed enrichment with positive regulation of cell cycle and classic oncogenic pathways in the high TIM expression phenotype, while keratinization pathways were negatively regulated and enriched. Further analysis showed that TIM was correlated with infiltration of multiple immune cells. Finally, IHC validated the differential expression of TIM in SKCM.ConclusionTIM might play a pivotal role in tumorigenesis of SKCM and is closely related to its prognosis.

Reactivation of methylation‐silenced PAX1 inhibits cervical cancer proliferation and migration via the WNT/TIMELESS pathway

“…TIMELESS is a member of the replication fork complex that promotes fork stabilization and prevents the collapse of the stalled replication fork 35,36 . TIMELESS is frequently overexpressed in multiple cancers 37‐39 . Recent research has shown that TIMELESS is overexpressed in CC and regulates cell proliferation and cisplatin sensitivity, suggesting that TIMELESS is an attractive target for cisplatin sensitizers in CC, 40 and the upregulation of TIMELESS is correlated with poor overall survival and disease‐free survival 41 .…”

“…35,36 TIMELESS is frequently overexpressed in multiple cancers. [37][38][39] Recent research has shown that TIMELESS is overexpressed in CC and regulates cell proliferation and cisplatin sensitivity, suggesting that TIMELESS is an attractive target for cisplatin sensitizers in CC, 40 and the upregulation of TIMELESS is correlated with poor overall survival and disease-free survival. 41 Our study is the first to reveal that PAX1 negatively regulates TIMELESS and suppresses the WNT signaling pathway via the TIMELESS/TCF/ β-catenin axis, which confirmed the role of a tumor suppressor gene for PAX1.…”