CDH11 Contributes to Bladder Cancer Progression via Regulation of Mitochondrial Energy Metabolism

TL;DR

This study shows that CDH11 promotes bladder cancer progression by regulating mitochondrial metabolism and could be a new therapeutic target.

Contribution

The study identifies CDH11 as a novel contributor to bladder cancer progression through mitochondrial energy metabolism regulation.

Findings

CDH11 knockdown significantly suppressed tumor growth in a mouse xenograft model.

CDH11 inhibition reduced mitochondrial activity in bladder cancer cells.

CDH11 is highly expressed in advanced bladder cancer and may influence the tumor microenvironment.

Abstract

Approximately 83,000 new cases of bladder cancer (BC) in the United States and 23,000 in Japan are confirmed per year, and the number of new BC cases increases every year. While the prognosis for localized cancer is favorable, treatment options for metastatic cancer are limited, and the prognosis is extremely poor.

Although the prevention of metastasis and the development of novel treatments for metastatic cancer are urgent challenges, the molecules contributing to BC metastasis and prognosis remain largely unknown. This study aimed to identify and analyze novel therapeutic target molecules for metastatic BC.

We collected gene expression datasets for BC cell lines from Gene Expression Omnibus and selected genes highly expressed in advanced BC cell lines. We also extracted genes highly expressed in metastatic BC patients from The Cancer Genome Atlas. We performed integrated analysis on these genes and combined it with Kaplan‐Meier analysis to identify genes involved in BC progression. The results revealed that CDH11 is involved in bladder cancer progression. We established CDH11 knockdown (KD) using shRNA in advanced bladder cancer cell lines and performed analyses of cell proliferation, invasion, and migration; gene expression analysis via RNA‐seq; tumor formation via xenografts; metabolic analysis using the Flux analyzer; and therapeutic effect analysis using low‐molecular‐weight compounds.

While CDH11 KD did not alter cell proliferation, invasion, or migration in vitro, CDH11 KD significantly suppressed tumor growth in an in vivo subcutaneous xenograft mouse model. RNA‐seq revealed that CDH11 KD cells decreased the expression of genes related to mitochondrial metabolism, and a metabolic flux analyzer confirmed decreased mitochondrial activity in the KD cells. Furthermore, use of a CDH11 inhibitor resulted in decreased mitochondrial activity in vitro, and CDH11 inhibitor resulted in inhibition of tumor growth in vivo.

Our findings suggest that CDH11 is highly expressed in advanced BC and may regulate the TME by interacting with other cell types and regulating mitochondrial energy metabolism.

These results suggest that CDH11 is involved in BC progression and is a potential therapeutic target.

CDH11 inhibition can suppress mitochondrial respiration in advanced bladder cancer cells and xenograft tumor progression.

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