Professor Lin Tianxin's team revealed a novel VEGF-C independent mechanism for exosomal long non-coding RNA-mediated lymphatic metastasis of bladder cancer

Recently, the latest research from Professor Lin Tianxin, "Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer ", was published on Journal of Clinical Investigation, revealed a novel VEGF-C independent mechanism of exosomal long non-coding RNA mediating lymph node metastasis of bladder cancer. Bladder cancer is one of the most common malignancies of male genitourinary system, which shows an increasing incidence rate year by year. Metastasis is the main cause of death in patients with bladder cancer, in which lymphatic metastasis is the most common way. Once lymph node metastasis occured, the 5-year survival rate of patients with bladder cancer decreases from 77.6% to 18.6%, thus lymph node metastasis has become an important independent predictor of prognosis in bladder cancer. Previous researches have demonstrated that infiltrated tumor cells can secrete VEGF-C to regulate lymphatic expansion, which further leads to more lymph fluid and malignant tumor cells entering the lymph node region, and promotes tumor growth and metastasis of distant lymph nodes. However, recent studies have found that some bladder cancer patients with low expression of VEGF-C can also occur lymphatic metastasis, suggesting that an VEGF-C independent pathway is involved in the regulation of lymph node metastasis of bladder cancer, but the specific molecular mechanism remains to be clarified. Funded by the National Key Research and Development program of China, the National Natural Science Foundation of China, the Natural Science Foundation of Guangdong and Science and Technology Program of Guangzhou, Professor Lin Tianxin's team of our hospital identified an exosomal lncRNA LNMAT2 through high-throughput sequencing, which was significantly related to lymphatic metastasis and poor prognosis of bladder cancer. In vivo and in vitro function experiments verified that exosomal LNMAT2 drastically promoted lymphangiogenesis and lymphatic metastasis of bladder cancer. Mechanismly, they demonstrated that LNMAT2 directly bound to hnRNPA2B1 to be packaged into exosomes under the mediation of hnRNPA2B1, which was internalized by lymphatic endothelial cells. Next, exosomal LNMAT2 bound to the promoter of PROX1, a pivotal protein for the neogenesis of lymphatic endothelial cells, to regulate its transcriptional activation. This study was the first to report that exosomal lncRNA could form a triplex structure with PROX1 promoter region, and upregulated its expression to promote lymphatic metastasis of bladder cancer. The clarification of this molecular mechanism revealed a crucial VEGF-C independent pathway in regulating lymphatic metastasis of bladder cancer, which not only provided a novel target for the development of targeted therapeutic drugs for lymphatic metastasis of bladder cancer, but also widened our insight for the prevention and treatment of lymphatic metastasis of malignant tumors. in the present study, Professor Lin Tianxin of our hospital, Professor Chen Rufu of Guangdong Provincial People's Hospital and Professor Huang Jian of Our hospital are the corresponding authors, and Dr. Chen Changhao, Dr. Luo Yuming, Dr. He Wang and Dr. Zhao Yue are the co-first authors.