STIL Acts as an Oncogenetic Driver in a Primary Cilia-Dependent Manner in Human Cancer.

Jingxian Li,Jianqiang Zhu,Shuai Li,Xinyu Gao,Zhihong Zhang,Yuanjiong Qi,Changwen Zhang,Zikun Yang,E Du,Xun Liu,Yang Liu

doi:10.3389/fcell.2022.804419

Abstract

SCL/TAL1 Interrupting locus (STIL) is a ciliary-related gene involved in regulating the cell cycle and duplication of centrioles in dividing cells. STIL has been found disordered in multiple cancers and driven carcinogenesis. However, the molecular mechanisms and biological functions of STIL in cancers remain ambiguous. Here, we systematically analyzed the genetic alterations, molecular mechanisms, and clinical relevance of STIL across >10,000 samples representing 33 cancer types in The Cancer Genome Atlas (TCGA) dataset. We found that STIL expression is up-regulated in most cancer types compared with their adjacent normal tissues. The expression dysregulation of STIL was affected by copy number variation, mutation, and DNA methylation. High STIL expression was associated with worse outcomes and promoted the progression of cancers. Gene Ontology (GO) enrichment analysis and Gene Set Variation Analysis (GSVA) further revealed that STIL is involved in cell cycle progression, Mitotic spindle, G2M checkpoint, and E2F targets pathways across cancer types. STIL expression was negatively correlated with multiple genes taking part in ciliogenesis and was positively correlated with several genes which participated with centrosomal duplication or cilia degradation. Moreover, STIL silencing could promote primary cilia formation and inhibit cell cycle protein expression in prostate and kidney cancer cell lines. The phenotype and protein expression alteration due to STIL silencing could be reversed by IFT88 silencing in cancer cells. These results revealed that STIL could regulate the cell cycle through primary cilia in tumor cells. In summary, our results revealed the importance of STIL in cancers. Targeting STIL might be a novel therapeutic approach for cancers.

Highlights

The primary cilia (PC) is a microtubule-based structure that protrudes from the surface of almost all mammalian cells and transduces extracellular signals to the cell body to regulate diverse cellular, developmental and physiological processes (Gluenz et al, 2010)
The body map depicted by the Gene expression profiling interactive analysis (GEPIA) website showed that SCL/TAL1 Interrupting locus (STIL) was widely expressed in human tissues (Figure 1A), which demonstrated that STIL is suitable for a pan-cancer analysis
Through a differential expression analysis, we found STIL was upregulated in multiple cancer tissues, including bladder, liver, gastric, ovarian, prostate, adrenal cortex, thyroid, breast, cervix, and skin cancer, compared with their normal tissues (Figure 1C), which was consistent with the results of The Cancer Genome Atlas (TCGA) dataset

Summary

Introduction

The primary cilia (PC) is a microtubule-based structure that protrudes from the surface of almost all mammalian cells and transduces extracellular signals to the cell body to regulate diverse cellular, developmental and physiological processes (Gluenz et al, 2010). STIL expression balance is closely involved in the formation of primary. PC-Related Protein STIL in Pan-Cancer cilia (Patwardhan et al, 2018). Complete loss of STIL expression results in no primary cilia. Even though in tumors with up-regulated STIL expression, the number of primary cilia still declines (Seeley et al, 2009; Basten et al, 2013; Nobutani et al, 2014; Du et al, 2018; Qie et al, 2020). The role of STIL for primary cilia formation still needs to explore in the tumor

Methods

Results

Conclusion