LMAN2 Promotes Breast Cancer Tumorigenesis and Drug Resistance by Interacting With MAPK9 via Activation of the MAPK Pathway

Abstract

ABSTRACT Introduction Breast cancer (BC) is the most prevalent malignancy among women worldwide. Lectin, mannose‐binding 2 (LMAN2) is a cargo receptor engaged in the transport and sorting of glycoproteins. Despite its ubiquity, the function and underlying mechanisms of LMAN2 in BC continue to elude understanding. Methods Multiple databases were employed to examine the expression of LMAN2 in breast cancer. Immunohistochemistry(IHC), qRT‐PCR, and Western blot were performed to quantify LMAN2 expression in BC cell lines and clinical samples. Heat map analysis and Kaplan–Meier analysis were used to analyze the correlation between LMAN2 and clinicopathological features. SiRNAs and overexpression plasmids were transfected into two BC cells to assess the effect of LMAN2 on malignant phenotypes. Coimmunoprecipitation and immunofluorescence were used to screen for potential interacting proteins. Additionally, tumor subcutaneous xenograft mode was constructed to explore tumor chemoresistance. Result LMAN2 expression was significantly higher in BC compared to that in matched, adjacent normal tissues, and its higher expression level was correlated with worse patient prognosis. In vitro, we found that LMAN2 functions as an oncogene, promoting BC cell proliferation, cell cycle progression, invasion, and chemoresistance while preventing apoptosis. Coimmunoprecipitation and colocalization experiments confirmed the direct binding of LMAN2 to MAPK9 in BC cells. Our investigation of signaling pathways suggested that LMAN2 is involved in the regulation of the MAPK signaling pathway, utilizing this pathway to confer cisplatin resistance. Furthermore, knockdown of LMAN2 improves the sensitivity of drug‐resistant BC cells to cisplatin (DDP) in vivo. Conclusion LMAN2 was a novel diagnostic and prognostic biomarker for BC that promotes chemoresistance via interaction with MAPK9 and activation of the MAPK pathway.

Keywords

• breast cancer
• LMAN2
• MAPK pathway
• MAPK9
• tumorigenesis