Journal Article

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

Shah, Ashu, Atri, Pranita, Batra, Surinder K., Maurya, Shailendra Kumar, Seshacharyulu, Parthasarathy, Chaudhary, Sanjib, Nasser, Mohd W., Ramakanth, Chirravuri Venkata, Appadurai, Muthamil Iniyan, Ponnusamy, Moorthy P., Lakshmanan, Imayavaramban, Nallasamy, Palanisamy, Marimuthu, Saravanakumar, Ganti, Apar Kishor, Lele, Subodh M.

2023

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Animals / Antibodies / Antigens / Biomedical and Life Sciences / Biomedicine / Breast cancer / CA-125 Antigen - genetics / CA-125 Antigen - metabolism / CA-125 Antigen - therapeutic use / Cancer Research / Cell cycle / Cell Line, Tumor / Cell migration / Cell Movement - genetics / Cell Proliferation - genetics / Clinical outcomes / Cloning / cMyc / Comparative analysis / DNA microarrays / ELAV-Like Protein 1 - genetics / ELAV-Like Protein 1 - metabolism / ELAVL1/HuR / Gene Expression Regulation, Neoplastic / Humans / HuR protein / Immunoprecipitation / Kinases / Laboratory animals / Lung cancer / Lung Neoplasms - pathology / Membrane Proteins - genetics / Metastases / Metastasis / Mice / MMP1 / Mucins / Oncology / Protein binding / Proteins / Ribonucleic acid / RNA / RNA-binding protein / Surgical Oncology / Therapeutic targets / Triple Negative Breast Neoplasms - pathology / UC16 / YB1 / YBX-1