As one of the most common malignancies in the urological system, urinary bladder cancer (UBC) ranks at the 9th position in cancer-related mortality in males worldwide. Low-grade, nonmuscle-invasive tumors account for 75% of newly diagnosed UBC cases, among which 15–20% of these patients advance toward muscle-invasive bladder cancers (MIBC). Unfortunately, patients with MIBC will progress to metastasis, with a low survival rate of 5-year prognosis. Hence, it is of great significance to characterize the molecular events that lead to UBC invasion and metastasis.

With the collaborations among Dr. YAN Jun from Model Animal Research Center, Nanjing University, Dr. HUANG Ruimin and Dr. ZHOU Hu from Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and Dr. GUO Hongqian from Nanjing Drum Tower Hospital, Nanjing University Medical School, scientists found a novel regulatory axis to drive UBC invasion and metastasis. The finding has been recently published online in Journal of Biological Chemistry.

In this study, the scientists utilized in vitro transwell screening assay to isolate UBC sublines with different invasive capacities from human UBC cell line 5637. Through proteomic analysis, Wnt7a, one of the Wnt ligands, was identified to be positively associated with UBC cell invasiveness. Notably, the expression level of Wnt7a from TCGA database is also correlated with lymph node and distal metastasis and Wnt7a overexpression predicts poor prognosis in human UBC patients.

Wnt7a may function as an oncogene or a tumor suppressor in different cancer types, and the role of Wnt7a in UBC remains largely unknown. “In contrast to its tumor suppressive effect on the lung cancer through non-canonical Wnt pathway, we find that Wnt7a overexpression is sufficient and essential for epithelial-to-mesenchymal transition and cell invasion of bladder cancer via the activation of canonical Wnt/β-catenin signaling,” said Dr. HUANG Ruimin, one of the lead authors of this study.

In addition, the overexpressed Wnt7a increased metastatic lesions to lung of UBC cells in nude mice. “Combined with aforementioned clinical relevance,” Dr. HUANG added, “we believe that Wnt7a overexpression plays a pivotal role in UBC metastasis.”

“Besides, we found the frequent down-regulation of miR-370-3p in UBC samples with lymph node metastasis, which accounts for the Wnt7a overexpression in UBC samples,” added Dr. YAN Jun, another co-lead author.

Though Wnt/β-catenin pathway has been implicated in UBC development, somatic mutations in this pathway were seldom reported. This novel miR-370-3p/Wnt7a regulatory axis reinforces the notion that the activation of Wnt/β-catenin pathway is important for UBC metastasis with promising opportunities for its prognosis and treatment.

This work was supported by the National Natural Science Foundation of China, Open Foundation of State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
Link to the article：http://www.jbc.org/content/293/18/6693.short

Figure: miR-370-3p/Wnt7a axis promotes urinary bladder cancer metastasis (Image by HUANG Ruimin)

Contact person:
Dr. HUANG Ruimin
E-mail: rmhuang@simm.ac.cn

(Credit: Huang Ruimin; Editor: PAN Peihua)