M2 Tumor Associate Macrophage- (TAM-) Derived lncRNA HISLA Promotes EMT Potential in Bladder Cancer

Tumor-associated macrophages (TAMs) are M2-like phenotype macrophages which contribute to the tumor progression in tumor microenvironment. The precise mechanisms of TAMs were intricated, and recently, it has been illustrated that TAM-derived exosomal lncRNAs played pivotal roles in the tumor development. In the present study, we investigated the role of TAM-derived exosomal lncRNA HISLA in bladder cancer.

Effects of TAM exosomes and exosomal lncRNA HISLA on migration and invasion in bladder cells were detected by wound healing assay, transwell assay, and western blot assay. Differential expression of lncRNA HISLA in exosomes derived from M0 or TAMs was examined by qRT-PCR. Western blot assay was used to classify the precise molecular mechanisms.

We found that TAM-derived exosomes significantly promote the migration and invasion abilities of bladder cells. Expression of epithelial-mesenchymal transition (EMT) markers was obviously affected by TAM exosome administration. Furthermore, we found that the expression of lncRNA HISLA was specifically elevated in TAM exosomes and TAM exosome-treated bladder cells. Silencing of lncRNA HISLA was found to suppress the processes of migration, invasion, and EMT in bladder cells. In addition, we found that β-catenin levels were downregulated, and Ser33 phosphorylated β-catenin levels were increased by HISLA siRNA treatment. At last, we found that HISLA stabilized β-catenin expression through preventing interaction between GSK3β and β-catenin.

In conclusion, our results investigated the prometastatic role of exosomal lncRNA HISLA derived from TAMs in bladder cancer and suggested TAM-derived HISLA as a promising therapeutic target of bladder cancer.