Scholarlink

Background <p>Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin lymphoma, contributing significantly to global health and economic challenges. Sodium-myoinositol cotransporter-1 (SMIT1) acts as an oncogene in different types of cancer. This study aimed to explore [<CitationRef CitationID="CR1">1</CitationRef>] the role of SMIT1 in DLBCL development, and [<CitationRef CitationID="CR2">2</CitationRef>] whether N6-Methyladenosine (m6A) modifications were responsible for high SMIT1 expression within DLBCL tissues.</p> Methods <p>Expression of SMIT1 was modulated by a eukaryotic SMIT1-expressing plasmid or a plasmid specific to SMIT1-targeting shRNA. The impacts of SMIT1 overexpression or knockdown on DLBCL cell proliferation, cell cycle, and apoptosis were evaluated using cell-counting-kit-8, flow cytometry and western blot assays. A DLBCL cell-derived tumor xenograft was established to further assess the tumorigenicity of SMIT1. qPCR, RIP-qPCR, MeRIP-qPCR, dual luciferase reporter and western blot assays were employed to explore whether high SMIT1 expression was associated with WTAP/YTHDF1-mediated m6A modifications.</p> Results <p>Bioinformatics analysis showed that high SMIT1 expression in DLBCL was positively associated with poor prognosis, survival-related markers and m6A methyltransferase Wilms tumor 1-associated protein (WTAP). SMIT1 overexpression supported proliferation and cell cycle progression of DLBCL cells, while its depletion induced proliferation suppression, G1-S phase arrest and apoptosis of DLBCL cells. Decreased myo-inositol, phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) contents and AKT phosphorylation level were observed after SMIT1 silencing, yet increased after SMIT1 overexpression in DLBCL cells. In vivo, SMIT1 silencing delayed tumor growth and induced AKT inactivation. SMIT1 silencing-induced anti-DLBCL role was partly weakened by the addition of AKT agonist SC-79. Furthermore, we found that upregulation of WTAP enhanced the SMIT1 m6A and mRNA levels. WTAP-regulated SMIT1 m6A was recognized and stabilized by YTH N6-Methyladenosine RNA Binding Protein F1 (YTHDF1) m6A reader.</p> Conclusions <p>Our study uncovers a novel oncogenic axis in DLBCL, where SMIT1’s carcinogenic potential is epigenetically modulated by WTAP/YTHDF1-mediated m6A methylation.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Sodium-myoinositol cotransporter-1 downstream of m6A methyltransferase WTAP exerts a potential carcinogenicity in diffuse large B-cell lymphoma progression

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月18日

查看全文
  • Xinyang Li,
  • Xiaowei He,
  • Ying Sun,
  • Wei Yang

摘要

Background

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin lymphoma, contributing significantly to global health and economic challenges. Sodium-myoinositol cotransporter-1 (SMIT1) acts as an oncogene in different types of cancer. This study aimed to explore [1] the role of SMIT1 in DLBCL development, and [2] whether N6-Methyladenosine (m6A) modifications were responsible for high SMIT1 expression within DLBCL tissues.

Methods

Expression of SMIT1 was modulated by a eukaryotic SMIT1-expressing plasmid or a plasmid specific to SMIT1-targeting shRNA. The impacts of SMIT1 overexpression or knockdown on DLBCL cell proliferation, cell cycle, and apoptosis were evaluated using cell-counting-kit-8, flow cytometry and western blot assays. A DLBCL cell-derived tumor xenograft was established to further assess the tumorigenicity of SMIT1. qPCR, RIP-qPCR, MeRIP-qPCR, dual luciferase reporter and western blot assays were employed to explore whether high SMIT1 expression was associated with WTAP/YTHDF1-mediated m6A modifications.

Results

Bioinformatics analysis showed that high SMIT1 expression in DLBCL was positively associated with poor prognosis, survival-related markers and m6A methyltransferase Wilms tumor 1-associated protein (WTAP). SMIT1 overexpression supported proliferation and cell cycle progression of DLBCL cells, while its depletion induced proliferation suppression, G1-S phase arrest and apoptosis of DLBCL cells. Decreased myo-inositol, phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) contents and AKT phosphorylation level were observed after SMIT1 silencing, yet increased after SMIT1 overexpression in DLBCL cells. In vivo, SMIT1 silencing delayed tumor growth and induced AKT inactivation. SMIT1 silencing-induced anti-DLBCL role was partly weakened by the addition of AKT agonist SC-79. Furthermore, we found that upregulation of WTAP enhanced the SMIT1 m6A and mRNA levels. WTAP-regulated SMIT1 m6A was recognized and stabilized by YTH N6-Methyladenosine RNA Binding Protein F1 (YTHDF1) m6A reader.

Conclusions

Our study uncovers a novel oncogenic axis in DLBCL, where SMIT1’s carcinogenic potential is epigenetically modulated by WTAP/YTHDF1-mediated m6A methylation.