Abstract
Cutaneous T cell lymphoma (CTCL) is a rare but potentially devastating primary cutaneous lymphoma. CTCL is characterized by localization of neoplastic T lymphocytes to the skin, with mycosis fungoides (MF) and its leukemic form, Sézary syndrome (SS) being the most common variants. Thymocyte selection-associated high-mobility group box (TOX) gene has been found to be highly expressed in MF and SS. It is reported that higher expression levels of TOX in patients will increase risks of disease progression and poor prognosis. However, the molecular events leading to these abnormalities have not been well understood. To better understand the molecular mechanism underlying TOX-mediated differentially expressed genes (DEGs) in CTCL, and to identify DEGs pathways triggered after knockdown of TOX gene in the CTCL cell line Hut78, we employed two shRNA-mediated lentiviruses to knock down TOX gene in the skin lymphoma cell line HuT78. RNA sequencing (RNAseq) analysis was applied to analyze DEGs, DEGs GO and their corresponding pathways. Knockdown of TOX can induce upregulation of 547 genes and downregulation of 649 genes, respectively. HOXC9 was the most significant downregulated gene. Most DEGs are enriched in malignancies and relate to the Wnt and mTOR signaling pathways, and therefore they can regulate cellular processes and induce different biological regulation. Transcriptome analysis of DEGs after knockdown of TOX in our study provides insights into the mechanism of TOX in CTCL and suggests candidate targets for therapy of CTCL.
Highlights
Cutaneous T cell lymphoma (CTCL) are a heterogeneous group of non-Hodgkin lymphoproliferative disorders characterized by accumulation and expansion of neoplastic T lymphocytes to the skin [28]
We found that most differentially expressed genes (DEGs) were enriched in cancer pathways, including breast cancer, gastric cancer and hepatocellular carcinoma, and that some DEGs were enriched in Wnt, mTOR signaling pathways and pathways in regulating pluripotency of stem cells
Thymocyte selection-associated high-mobility group box (TOX) is aberrantly overexpressed in CTCLs, such as mycosis fungoides (MF) and Sézary syndrome (SS)
Summary
CTCLs are a heterogeneous group of non-Hodgkin lymphoproliferative disorders characterized by accumulation and expansion of neoplastic T lymphocytes to the skin [28]. MF and SS constitute two main subtypes of CTCL. While MF primarily affects the skin, SS is characterized by the presence of circulating malignant Sézary cells. Accumulative evidence indicates that defects in apoptosis and cell cycle control are critical in disease pathogenesis [5, 21], the molecular mechanism leading to these abnormalities has not been well understood yet. The TOX gene was firstly described in 2002 [27], as a part of the superfamily of high-mobility group box proteins that act as regulators of gene expression, mainly by modifying the chromatin structure [10, 27]. TOX mRNA is most abundant in the thymus, liver and brain [27].
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