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MUC16 promotes triple-negative breast cancer lung metastasis by modulating RNA-binding protein ELAVL1/HUR

Authors :
Sanjib Chaudhary
Muthamil Iniyan Appadurai
Shailendra Kumar Maurya
Palanisamy Nallasamy
Saravanakumar Marimuthu
Ashu Shah
Pranita Atri
Chirravuri Venkata Ramakanth
Subodh M. Lele
Parthasarathy Seshacharyulu
Moorthy P. Ponnusamy
Mohd W. Nasser
Apar Kishor Ganti
Surinder K. Batra
Imayavaramban Lakshmanan
Source :
Breast Cancer Research, Vol 25, Iss 1, Pp 1-15 (2023)
Publication Year :
2023
Publisher :
BMC, 2023.

Abstract

Abstract Background Triple-negative breast cancer (TNBC) is highly aggressive with an increased metastatic incidence compared to other breast cancer subtypes. However, due to the absence of clinically reliable biomarkers and targeted therapy in TNBC, outcomes are suboptimal. Hence, there is an urgent need to understand biological mechanisms that lead to identifying novel therapeutic targets for managing metastatic TNBC. Methods The clinical significance of MUC16 and ELAVL1 or Hu antigen R (HuR) was examined using breast cancer TCGA data. Microarray was performed on MUC16 knockdown and scramble TNBC cells and MUC16-associated genes were identified using RNA immunoprecipitation and metastatic cDNA array. Metastatic properties of MUC16 were evaluated using tail vein experiment. MUC16 and HuR downstream pathways were confirmed by ectopic overexpression of MUC16-carboxyl-terminal (MUC16-Cter), HuR and cMyc as well as HuR inhibitors (MS-444 and CMLD-2) in TNBC cells. Results MUC16 was highly expressed in TNBC and correlated with its target HuR. Depletion of MUC16 showed decreased invasion, migration, and colony formation abilities of human and mouse TNBC cells. Mice injected with MUC16 depleted cells were less likely to develop lung metastasis (P = 0.001). Notably, MUC16 and HuR were highly expressed in the lung tropic TNBC cells and lung metastases. Mechanistically, we identified cMyc as a HuR target in TNBC using RNA immunoprecipitation and metastatic cDNA array. Furthermore, MUC16 knockdown and pharmacological inhibition of HuR (MS-444 and CMLD-2) in TNBC cells showed a reduction in cMyc expression. MUC16-Cter or HuR overexpression models indicated MUC16/HuR/cMyc axis in TNBC cell migration. Conclusions Our study identified MUC16 as a TNBC lung metastasis promoter that acts through HuR/cMyc axis. This study will form the basis of future studies to evaluate the targeting of both MUC16 and HuR in TNBC patients.

Details

Language :
English
ISSN :
1465542X
Volume :
25
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Breast Cancer Research
Publication Type :
Academic Journal
Accession number :
edsdoj.89f442b49cf48b58554e7cbf76ee1f0
Document Type :
article
Full Text :
https://doi.org/10.1186/s13058-023-01630-7