Nerves are important pathological elements of the microenvironment of tumors, including those in pancreatic, colon and rectal, prostate, head and neck, and breast cancers. Recent studies have associated perineural invasion with tumor progression and poor outcomes. In turn, tumors drive the reprogramming of neurons to recruit new nerve fibers. Therefore, the crosstalk between nerves and tumors is the hot topic and trend in current cancer investigations. Herein, we reviewed recent studies presenting direct supporting evidences for a better understanding of nerve–tumor interactions.
Background
Sunitinib resistance can be classified into primary and secondary resistance. While accumulating research has indicated several underlying factors contributing to sunitinib resistance, the precise mechanisms in renal cell carcinoma are still unclear.
Methods
RNA sequencing and m6A sequencing were used to screen for functional genes involved in sunitinib resistance. In vitro and in vivo experiments were carried out and patient samples and clinical information were obtained for clinical analysis.
Results
We identified a tumor necrosis factor receptor-associated factor, TRAF1, that was significantly increased in sunitinib-resistant cells, resistant cell-derived xenograft (CDX-R) models and clinical patients with sunitinib resistance. Silencing TRAF1 increased sunitinib-induced apoptotic and antiangiogenic effects. Mechanistically, the upregulated level of TRAF1 in sunitinib-resistant cells was derived from increased TRAF1 RNA stability, which was caused by an increased level of N6-methyladenosine (m6A) in a METTL14-dependent manner. Moreover, in vivo adeno-associated virus 9 (AAV9) -mediated transduction of TRAF1 suppressed the sunitinib-induced apoptotic and antiangiogenic effects in the CDX models, whereas knockdown of TRAF1 effectively resensitized the sunitinib-resistant CDXs to sunitinib treatment.
Conclusions
Overexpression of TRAF1 promotes sunitinib resistance by modulating apoptotic and angiogenic pathways in a METTL14-dependent manner. Targeting TRAF1 and its pathways may be a novel pharmaceutical intervention for sunitinib-treated patients.
Clear cell renal cell carcinoma (ccRCC) is the most lethal urological cancer and is characterized by a high rate of metastasis and relapse. N6-Methyladenosine (m 6 A) is implicated in various stages of cancer development. However, a thorough understanding of m 6 A-modified lncRNAs in ccRCC is lacking. The results showed that METTL14 had decreased expression in ccRCC tissues. In addition, the expression of METTL14 was negatively correlated to the prognosis, stage, and ccRCC tumor grade. The silencing of METTL14 was shown to significantly increase metastasis in vitro and in vivo. Highthroughput methylated RNA immunoprecipitation sequencing (MeRIP-seq) showed that the m 6 A levels of Lnc-LSG1 could be regulated by METTL14. Lnc-LSG1 can directly bind to ESRP2 protein and promote ESRP2 degradation via facilitating ESRP2 ubiquitination. However, m 6 A modification on Lnc-LSG1 can block the interaction between Lnc-LSG1 and ESRP2 via the m 6 A reader, YTHDC1. Taken together, our findings unraveled the novel mechanism of METTL14 inhibiting ccRCC progression, and explored the correlation between m 6 A and lncRNA in ccRCC for the first time.
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