Background: Circular RNA (circRNA) is a type of circular endogenous RNA produced by special selective splicing and participates in progression of diverse diseases. However, the role of circRNA in clear cell renal cell carcinoma (ccRCC) is still rarely reported. Methods: We detected lower circ-AKT3 expression in ccRCC using the circular RNA microarray. Then, qPCR array was applied to verify the expression of circ-AKT3 in between 60 ccRCC tissues and adjacent normal tissues, as well as ccRCC cell lines and human normal kidney cell (HK-2). We investigated the function of circ-AKT3 in ccRCC in vitro and in vivo and detected underlying mechanisms by Western blotting, bioinformatic analysis, RNA pull-down assay and luciferase reporter assay. Results: Circ-AKT3 was verified significantly downregulated in ccRCC. Knockdown of circ-AKT3 promoted ccRCC migration and invasion, while overexpression of circ-AKT3 suppressed ccRCC metastasis. Further, circ-AKT3/miR-296-3p/E-cadherin axis was shown responsible for circ-AKT3 inhibiting ccRCC metastasis. Conclusion: Circ-AKT3 suppresses ccRCC metastasis by enforcing E-cadherin expression through competitively binding miR-296-3p. Circ-AKT3 may therefore serve as a novel therapeutic to better suppress ccRCC metastasis.

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 (m⁶A) is implicated in various stages of cancer development. However, a thorough understanding of m⁶A-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. High-throughput methylated RNA immunoprecipitation sequencing (MeRIP-seq) showed that the m⁶A 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, m⁶A modification on Lnc-LSG1 can block the interaction between Lnc-LSG1 and ESRP2 via the m⁶A reader, YTHDC1. Taken together, our findings unraveled the novel mechanism of METTL14 inhibiting ccRCC progression, and explored the correlation between m⁶A and lncRNA in ccRCC for the first time.

Prostate cancer is one of the most prevalent forms of cancer around the world. Androgen-deprivation treatment and chemotherapy are the curative approaches used to suppress prostate cancer progression. However, drug resistance is extensively and hard to overcome even though remarkable progress has been made in recent decades. Noncoding RNAs, such as miRNAs, lncRNAs, and circRNAs, are a group of cellular RNAs which participate in various cellular processes and diseases. Recently, accumulating evidence has highlighted the vital role of non-coding RNA in the development of drug resistance in prostate cancer. In this review, we summarize the important roles of these three classes of noncoding RNA in drug resistance and the potential therapeutic applications in this disease.

A lipid droplet (LD) is an organelle that consists of a phospholipid monolayer and a neutral lipid core, with proteins embedded in or attached to its surface. Until recently, cancers had long been regarded as genetic disorders with the abnormal activation of oncogenes and inactivation of tumor suppressor genes before their quality of a metabolic disorder began to be recognized. The last decade has witnessed the recognition of several metabolic characteristics of cancer cells, among which one is the accumulation of lipid droplets; therefore, attention has been given to exploring the role of LDs in carcinomas. In addition, there has been a remarkable expansion in understanding the complexity of LD's function in cellular homeostasis, including but not limited to energy supply, endoplasmic reticulum (ER) stress and oxidative stress management, or lipotoxicity alleviation. Thus, lipid droplet-associated proteins, which to a great extent determine the dynamics of a lipid droplet, have attracted the interest of numerous cancer researchers and their potential as cancer diagnostic biomarkers and therapeutic targets has been affirmed by emerging evidence. In this review, we systematically summarize the critical role of LDs in cancer and then focus on four categories of lipid droplet-associated proteins having the most direct influence on LD biosynthesis (diacylglycerol acyltransferase 1 (DGAT1) and diacylglycerol acyltransferase 2 (DGAT2)), degradation (adipose triglyceride lipase (ATGL)), and two renowned protein families on the LD surface (perilipins and cell death-inducing DNA fragmentation factor alpha-like effectors (CIDEs)). In this way, we aim to highlight their important role in tumor progression and their potential in clinical applications.