Renal cell carcinoma (RCC) is an aggressive genitourinary malignancy which has been associated with a poor prognosis, particularly in patients with metastasis, its major subtypes being clear cell RCC (ccRCC), papillary PCC (pRCC) and chromophobe RCC (chRCC). The presence of intracellular lipid droplets (LDs) is considered to be a hallmark of ccRCC. The importance of an altered lipid metabolism in ccRCC has been widely recognized. The elongation of very‑long‑chain fatty acid (ELOVL) catalyzes the elongation of fatty acids (FAs), modulating lipid composition, and is required for normal bodily functions. However, the involvement of elongases in RCC remains unclear. In the present study, the expression of ELOVL2 in ccRCC was examined; in particular, high levels of seven ELOVL isozymes were observed in primary tumors. Of note, elevated ELOVL2 expression levels were observed in ccRCC, as well as in pRCC and chRCC. Furthermore, a higher level of ELOVL2 was significantly associated with the increased incidence of a poor prognosis of patients with ccRCC and pRCC. The CRISPR/Cas9‑mediated knockdown of ELOVL2 resulted in the suppression of the elongation of long‑chain polyunsaturated FAs and increased LD production in renal cancer cells. Moreover, ELOVL2 ablation resulted in the suppression of cellular proliferation via the induction of apoptosis in vitro and the attenuation of tumor growth in vivo. On the whole, the present study provides new insight into the tumor proliferation mechanisms involving lipid metabolism, and suggests that ELOVL2 may be an attractive novel target for RCC therapy.

Radical cystectomy is the gold standard treatment for muscle invasive bladder cancer, but some patients have medically inoperable disease or refuse cystectomy to preserve their bladder function. Bladder preservation therapy with transurethral resection of the bladder tumor and concurrent chemoradiotherapy, known as trimodal treatment, is regarded to be a curative-intent alternative to radical cystectomy for patients with muscle invasive bladder cancer during the past decade. After the development of immune checkpoint inhibitors, a world-changing breakthrough occurred in the field of metastatic urothelial carcinoma and many clinical trials have been conducted against non-muscle invasive bladder cancer. Interestingly, preclinical and clinical studies against other malignancies have shown that immune checkpoint inhibitors interact with the radiation-induced immune reaction. As half of the patients with muscle invasive bladder cancer are elderly, and some have renal dysfunction, not only as comorbidity but also because of hydronephrosis caused by their tumors, immune checkpoint inhibitors are expected to become part of a new therapeutic approach for combination treatment with radiotherapy. Accordingly, clinical trials testing immune checkpoint inhibitors have been initiated to preserve bladder for muscle invasive bladder cancer patients using radiation and immune checkpoint inhibitors with/without chemotherapy. The objective of this review is to summarize the evidence of trimodal therapy for muscle invasive bladder cancer during the past decade and to discuss the future directions of bladder preservation therapy in immuno-oncology era.

Renal cell carcinoma (RCC) features altered lipid metabolism and accumulated polyunsaturated fatty acids (PUFAs). Elongation of very long–chain fatty acid (ELOVL) family enzymes catalyze fatty acid elongation, and ELOVL5 is indispensable for PUFAs elongation, but its role in RCC progression remains unclear. Here, we show that higher levels of ELOVL5 correlate with poor RCC clinical prognosis. Liquid chromatography/electrospray ionization‐tandem mass spectrometry analysis showed decreases in ELOVL5 end products (arachidonic acid and eicosapentaenoic acid) under CRISPR/Cas9‐mediated knockout of ELOVL5 while supplementation with these fatty acids partially reversed the cellular proliferation and invasion effects of ELOVL5 knockout. Regarding cellular proliferation and invasion, CRISPR/Cas9‐mediated knockout of ELOVL5 suppressed the formation of lipid droplets and induced apoptosis via endoplasmic reticulum stress while suppressing renal cancer cell proliferation and in vivo tumor growth. Furthermore, CRISPR/Cas9‐mediated knockout of ELOVL5 inhibited AKT Ser473 phosphorylation and suppressed renal cancer cell invasion through chemokine (C‐C motif) ligand‐2 downregulation by AKT‐mTOR‐STAT3 signaling. Collectively, these results suggest that ELOVL5‐mediated fatty acid elongation promotes not only cellular proliferation but also invasion in RCC.

The Tumor-Node-Metastasis (TNM) staging system, jointly developed by the American Joint Commission on Cancer (AJCC) and the Union for International Cancer Control (UICC), is widely employed in clinical practice and research on patients with cancer. The definitions of TNM classification have recently been changed, improving patient stratification for management and prognosis. As the feature of new editions, biomarkers which are necessary for the stratification of patients are included to adapt for personalized medicine. Although it would be ideal for the AJCC and UICC have identical TNM staging systems, there are some differences between these two publications. In this review, we introduce the significant changes and differences in the eighth edition of the AJCC and UICC TNM staging systems for urologic cancers and summarize the evidence supporting these changes.

Cold-inducible RNA-binding protein (CIRP) and RNA-binding motif protein 3 (RBM3) are two evolutionarily conserved RNA-binding proteins that are structurally related to hnRNPs and upregulated in response to moderately low temperatures in mammalian cells. Although contributions of splicing efficiency, the gene promoters activated upon mild hypothermia and the transcription factor Sp1 to induction of CIRP have been reported, precise mechanisms by which hypothermia and other stresses induce the expression of mammalian cold-inducible proteins (CIPs) are poorly understood. By screening the serine/arginine-rich splicing factors (SRSFs), we report that the transcript and protein levels of SRSF5 were increased in mammalian cells cultured at 32 °C. Expression of SRSF5 as well as CIRP and RBM3 were also induced by DNA damage, hypoxia, cycloheximide and hypotonicity. Immunohistochemical studies demonstrated that SRSF5 was constitutively expressed in male germ cells and the level was decreased in human testicular germ cell tumors. SRSF5 facilitated production of p19 H-RAS, and increased sensitivity to doxorubicin in human U-2 OS cells. Induction of CIPs was dependent on transient receptor potential vanilloid 4 (TRPV4) channel protein, but seemed independent of its ion channel activity. These findings indicate a previously unappreciated role for the TRP protein in linking environmental stress to splicing.

A hallmark of clear cell renal cell carcinoma (ccRCC) is the presence of intracellular lipid droplets (LD) and it is assumed that phosphatidic acid (PA) produced by phospholipase D (PLD) plays some role in theLDformation. However, little is known about the significance ofPLDin ccRCC. In this study, we examined the expression levels ofPLDin ccRCC. The classical mammalian isoforms ofPLDarePLD1 andPLD2, and the levels of bothmRNAwere higher at the primary tumor sites than in normal kidney tissues. Similarly, bothPLDwere significantly abundant in tumor cells as determined by analysis using immunohistochemical staining. Importantly, a higher level ofPLDwas significantly associated with a higher tumor stage and grade. BecausePLD2 knockdown effectively suppressed the cell proliferation and invasion of ccRCCas compared withPLD1 in vitro, we examined the effect ofPLD2 in vivo. Notably, shRNA‐mediated knockdown ofPLD2 suppressed the growth and invasion of tumors in nude mouse xenograft models. Moreover, the higher expression ofPLD2 was significantly associated with poorer prognosis in 67 patients. As for genes relating to the tumor invasion ofPLD2, we found that angiogenin (ANG) was positively regulated byPLD2. In fact, the expression levels ofANGwere elevated in tumor tissues as compared with normal kidney and the inhibition ofANGactivity with a neutralizing antibody significantly suppressed tumor invasion. Overall, we revealed for the first time thatPLD2‐producedPApromoted cell invasion through the expression ofANGin ccRCCcells.