Scholarlink

Background <p>Dysregulated lipid metabolism and chemoresistance are key drivers of breast cancer progression. Lectin, mannose-binding 2 (LMAN2) is frequently overexpressed in human breast tumors and functions as an oncogenic driver. However, whether LMAN2 contributes to chemoresistance remains unknown.</p> Methods <p>We integrated multi-omics data from 1,085 primary tumors and matched normal tissues (from GEPIA and UALCAN) with functional studies in breast cancer cell lines and a doxorubicin (ADM)-treated nude mouse xenograft model. LMAN2 expression was modulated via siRNA/shRNA-mediated silencing or lentivirus-driven overexpression. Cellular phenotypes-including proliferation, migration, apoptosis, and response to ADM were systematically assessed. RNA-sequencing, untargeted lipidomics, and rescue experiments identified stearoyl-CoA desaturase (SCD) as a critical downstream effector. IC50 shifts and epistasis analysis further validated the role of the LMAN2/SCD axis in chemoresistance.</p> Results <p><i>LMAN2</i> mRNA was elevated across all molecular subtypes (luminal &gt; HER2 &gt; triple-negative) and predicted poorer overall survival (<i>P</i> = 5 × 10<sup>−4</sup>) and progression-free survival (<i>P</i> = 0.018). Silencing LMAN2 reduced clonogenicity by ~ 45% and migration by 37–63%, whereas overexpression increased cell viability by 1.4–1.7-fold and doubled motility. Knockdown of <i>LMAN2</i> decreased the ADM IC50 by 4–5 fold, abolished macroscopic colony formation, and elevated apoptosis rates from 15 to 18% to 39–41%; these effects were reversed upon LMAN2 overexpression. In vivo, shLMAN2 combined with ADM reduced tumor volume and weight by 72% and 75%, respectively, compared to ADM alone (<i>P</i> &lt; 0.001). Mechanistically, LMAN2 loss downregulated genes involved in “cholesterol homeostasis” and reduced total cellular cholesterol by 24%. SCD emerged as the most significantly downregulated enzyme and fully rescued the phenotypic and chemoresistance effects resulting from LMAN2 modulation. Epistasis experiments confirmed that LMAN2-mediated chemoresistance strictly depends on SCD function.</p> Conclusions <p>LMAN2 is a robust prognostic biomarker that promotes breast tumor growth and anthracycline resistance by enabling SCD-dependent lipid desaturation. Therapeutic targeting of the LMAN2/SCD axis represents a promising strategy to overcome chemoresistance in breast cancer.</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

LMAN2 promotes breast cancer progression and deduces cell sensitivity to doxorubicin through stearoyl-CoA desaturase

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月8日

查看全文
  • Changjiao Yan,
  • Fengqiang Cui,
  • Chutuo Liu,
  • Rui Ling,
  • Meiling Huang,
  • Ting Wang

摘要

Background

Dysregulated lipid metabolism and chemoresistance are key drivers of breast cancer progression. Lectin, mannose-binding 2 (LMAN2) is frequently overexpressed in human breast tumors and functions as an oncogenic driver. However, whether LMAN2 contributes to chemoresistance remains unknown.

Methods

We integrated multi-omics data from 1,085 primary tumors and matched normal tissues (from GEPIA and UALCAN) with functional studies in breast cancer cell lines and a doxorubicin (ADM)-treated nude mouse xenograft model. LMAN2 expression was modulated via siRNA/shRNA-mediated silencing or lentivirus-driven overexpression. Cellular phenotypes-including proliferation, migration, apoptosis, and response to ADM were systematically assessed. RNA-sequencing, untargeted lipidomics, and rescue experiments identified stearoyl-CoA desaturase (SCD) as a critical downstream effector. IC50 shifts and epistasis analysis further validated the role of the LMAN2/SCD axis in chemoresistance.

Results

LMAN2 mRNA was elevated across all molecular subtypes (luminal > HER2 > triple-negative) and predicted poorer overall survival (P = 5 × 10−4) and progression-free survival (P = 0.018). Silencing LMAN2 reduced clonogenicity by ~ 45% and migration by 37–63%, whereas overexpression increased cell viability by 1.4–1.7-fold and doubled motility. Knockdown of LMAN2 decreased the ADM IC50 by 4–5 fold, abolished macroscopic colony formation, and elevated apoptosis rates from 15 to 18% to 39–41%; these effects were reversed upon LMAN2 overexpression. In vivo, shLMAN2 combined with ADM reduced tumor volume and weight by 72% and 75%, respectively, compared to ADM alone (P < 0.001). Mechanistically, LMAN2 loss downregulated genes involved in “cholesterol homeostasis” and reduced total cellular cholesterol by 24%. SCD emerged as the most significantly downregulated enzyme and fully rescued the phenotypic and chemoresistance effects resulting from LMAN2 modulation. Epistasis experiments confirmed that LMAN2-mediated chemoresistance strictly depends on SCD function.

Conclusions

LMAN2 is a robust prognostic biomarker that promotes breast tumor growth and anthracycline resistance by enabling SCD-dependent lipid desaturation. Therapeutic targeting of the LMAN2/SCD axis represents a promising strategy to overcome chemoresistance in breast cancer.