A Pan-Cancer Analysis of Cystatin E/M Reveals Its Dual Functional Effects and Positive Regulation of Epithelial Cell in Human Tumors.

Zhengyang Xu,Dahua Xu,Hong Wang,Dongqin Qiu,Kongning Li,Zhonglin Mu,Shun Ding,Xiaoman Bi,Meng Cao,Xiaorong Yu

doi:10.3389/fgene.2021.733211

Zhengyang Xu, Dahua Xu + Show 8 more

Open Access

https://doi.org/10.3389/fgene.2021.733211

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Abstract

Cystatin E/M (CST6), a representative cysteine protease inhibitor, plays both tumor-promoting and tumor-suppressing functions and is pursued as an epigenetically therapeutic target in special cancer types. However, a comprehensive and systematic analysis for CST6 in pan-cancer level is still lacking. In the present study, we explored the expression pattern of CST6 in multiple cancer types across ∼10,000 samples from TCGA (The Cancer Genome Atlas) and ∼8,000 samples from MMDs (Merged Microarray-acquired Datasets). We found that the dynamic expression alteration of CST6 was consistent with dual function in different types of cancer. In addition, we observed that the expression of CST6 was globally regulated by the DNA methylation in its promoter region. CST6 expression was positively correlated with the epithelial cell infiltration involved in epithelial-to-mesenchymal transition (EMT) and proliferation. The relationship between CST6 and tumor microenvironment was also explored. In particular, we found that CST6 serves a protective function in the process of melanoma metastasis. Finally, the clinical association analysis further revealed the dual function of CST6 in cancer, and a combination of the epithelial cell infiltration and CST6 expression could predict the prognosis for SKCM patients. In summary, this first CST6 pan-cancer study improves the understanding of the dual functional effects on CST6 in different types of human cancer.

Highlights

Cystatin E/M is a member of the cystatin superfamily that performs physiological inhibitors of lysosomal cysteine proteases through forming high-affinity reversible complexes (Turk and Bode, 1991)
The patients with HPV infection showed a lower expression level of CST6 in head and neck squamous cell carcinoma (HNSC), and the patients with metastasis status showed a lower expression in skin cutaneous melanoma (SKCM)
The tumor-suppressive function of CST6 has been reported in lung cancer (Zhong et al, 2007), melanoma (Briggs et al, 2010), and renal cell carcinoma (Morris et al, 2010), which agreed with the loss expression of CST6 in these cancer types

Summary

Introduction

Cystatin E/M ( known as CST6) is a member of the cystatin superfamily that performs physiological inhibitors of lysosomal cysteine proteases through forming high-affinity reversible complexes (Turk and Bode, 1991). Increasing evidence has demonstrated the dual functional effects of CST6 in cancer progress (Lalmanach et al, 2021). Function of CST6 in Tumors could rescue mice from bone metastasis by suppressing proliferation, migration, and invasion (Jin et al, 2012). In contrast to the protective function, Hosokawa et al (2008) found that the upregulated expression of CST6 promoted tumor growth in vitro and in vivo in pancreatic ductal adenocarcinoma. CST6 was shown overexpressed in triple-negative breast cancer and oral cancer, facilitating the tumor metastatic process (Vigneswaran et al, 2003; Li et al, 2018). A comprehensive research about the expression pattern and functional effects of CST6 in pan-cancer level is still lacking

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