Clear cell renal cell carcinoma (ccRCC) is a complex disease with remarkable immune and metabolic heterogeneity. Here we perform genomic, transcriptomic, proteomic, metabolomic and spatial transcriptomic and metabolomic analyses on 100 patients with ccRCC from the Tongji Hospital RCC (TJ-RCC) cohort. Our analysis identifies four ccRCC subtypes including De-clear cell differentiated (DCCD)-ccRCC, a subtype with distinctive metabolic features. DCCD cancer cells are characterized by fewer lipid droplets, reduced metabolic activity, enhanced nutrient uptake capability and a high proliferation rate, leading to poor prognosis. Using single-cell and spatial trajectory analysis, we demonstrate that DCCD is a common mode of ccRCC progression. Even among stage I patients, DCCD is associated with worse outcomes and higher recurrence rate, suggesting that it cannot be cured by nephrectomy alone. Our study also suggests a treatment strategy based on subtype-specific immune cell infiltration that could guide the clinical management of ccRCC.

Background: Accumulating evidence suggests a tumor suppressive role for miR-34a in human carcinogenesis. However, its precise biological role remains largely elusive. This study aimed to reveal the association of the miR-34a expression and its modulation of sensitivity to cisplatin in muscle-invasive bladder cancer (MIBC). Methods: miR-34a expression in MIBC cell lines and patient tissues was investigated using qPCR. The methylation analysis of miR-34a promoter region was performed by MassARRAY. Synthetic short single or double stranded RNA oligonucleotides and lentiviral vector were used to regulate miR-34a expression in MIBC cells to investigate its function in vitro and in vivo. Results: miR-34a expression was frequently decreased in MIBC tissues and cell lines through promoter hypermethylation while it was epigenetically increased in MIBC cells following cisplatin treatment. Increased miR-34a expression significantly sensitized MIBC cells to cisplatin and inhibited the tumorigenicity and proliferation of cancer cells in vitro and in vivo. Furthermore, we identified CD44 as being targeted by miR-34a in MIBC cells following cisplatin treatment, and increased CD44 expression could efficiently reverse the effect of miR-34a on MIBC cell proliferation, colongenic potential and chemosensitivity. Conclusions: Cisplatin-based chemotherapy induced demethylation of miR-34a promoter and increased miR-34a expression, which in turn sensitized MIBC cells to cisplatin and decreased the tumorigenicity and proliferation of cancer cells that by reducing the production of CD44.

Castration-resistant prostate cancer (CRPC) is an advanced stage of prostate cancer that can progress rapidly even in patients treated with castration. Previously, we found that tumor-associated macrophages (TAM) can be recruited by CSF-1 secreted by docetaxel-treated prostate cancer cells and promote the survival of cancer cells in response to chemotherapy. The inhibition of CSF-1R can impede this effect and significantly prolong survival in xenograft mice. However, the actual mechanism of how TAM improves cancer cell survival still remains elusive and controversial. Here, for the first time, we found that the enhanced survival of cancer cells achieved by TAM was mainly mediated by CXCR4 activation from the increased secretion of CXCL12 from CSF-1 activated TAM. This finding helps to clarify the mechanism of chemoresistance for second-line chemotherapy using docetaxel, facilitating the development of novel drugs to overcome immune tolerance in castration-resistant prostate cancer.

Bladder cancer is one of the most common cancers worldwide. Fibulin-1, a multi-functional extracellular matrix protein, has been demonstrated to be involved in many kinds of cancers, while its function in bladder cancer remains unclear. So here we investigated the expression and function of fibulin-1 in Bladder cancer. We used real-time PCR, Western blot analysis and immunohistochemistry to determine the expression of fibulin-1 in Bladder cancer cells and patient tissues respectively. Methylation-specific PCR and quantitative sequencing were used to examine the methylation status of FBLN1 gene promoter. Eukaryotic expression plasmid and lentiviral vector were used to overexpress fibulin-1 in Bladder cancer cells 5637, HT-1376 to investigate its function in vitro and in vivo. We identified that fibulin-1 was significantly down-regulated in bladder cancer, and its dysregulation was associated with non-muscle-invasive bladder cancer (NMIBC) grade and recurrence. The promoter region of FBLN1 was generally methylated in bladder cancer cell lines and tissues, further investigation in patient tissues showed that the methylation status was associated with the fibulin-1 expression. Overexpression of fibulin-1 significantly suppressed tumor growth, induced tumor cell apoptosis, decreased cell motility, and inhibited angiogenesis in cultured bladder cancer cells and xenograft tumor in nude mice. Altogether, our results indicated that fibulin-1 expression is associated with NMIBC grade and recurrence, it is epigenetically down-regulated and functions as a tumor suppressor gene and angiogenesis inhibitor in bladder cancer.

Background: Tumor cells exhibit enhanced metabolism of nutrients to satisfy the demand of sustained proliferation in vivo. Seminal reports have presented evidence that tryptophan (Trp) metabolic reprogramming induced by aberrant indoleamine 2,3-dioxygenases could promote tumor development in several cancer types. However, the underlying mechanism of Trp metabolism associated tumor progression is not fully understood. Materials and methods: Prostatic cell lines LNCaP and VCaP were purchased from the Cell Bank of the Chinese Academy of Sciences (China). Human prostatic tumor tissue samples were obtained from the Tongji Hospital. Female NOD-SCID mice (6 ~ 8 weeks) were purchased from Huafukang Co. (China) and raised in SPF room. Commercial kits and instruments were used for cell apoptosis analysis, real-time PCR, western blotting, ELISA analysis and other experiments. Result: Comparing the tumor tissues from prostatic cancer patients, we found elevated expression of tryptophan 2, 3-dioxygenase 2 (TDO2), and elevated Trp metabolism in chemo-resistant tumor tissues. In vitro, overexpression of TDO2 significantly promoted the Trp metabolism in prostatic cancer cell lines LNCaP and VCap, resulting in the multidrug resistance development. Mechanistically, we demonstrated that Trp metabolite kynurenine (Kyn) promoted the upregulation and nuclear translocation of transcription factor aryl hydrocarbon receptor (AhR). Subsequently, AhR collaborated with NF-κB to facilitate the activation of c-Myc. In turn, c-Myc promoted the up-regulation of ATP-binding cassette (ABC) transporters and Trp transporters, thereby contributing to chemoresistance and strengthened Trp metabolism in prostatic cancer. Interrupt of Trp/TDO2/Kyn/AhR/c-Myc loop with c-Myc inhibitor Mycro-3 efficiently suppressed the chemoresistance and improved the outcome of chemotherapy, which described a new strategy in clinical prostatic cancer treatment. Conclusion: Our study demonstrates that elevated TOD2 expression promoted Trp metabolism and metabolite Kyn production, thus resulting in the activation of AhR/c-Myc/ABC-SLC transporters signaling pathway. Interrupt of Trp metabolism/c-Myc loop efficiently suppressed the drugs resistance induced by TDO2, which represented potential target to improve the outcome in drug-resistant prostatic cancer treatment.

Lower ureteric stones and lower urinary tract symptoms are common in urology.Drug treatment is one of standard therapy,but the efficacy was controversial.Thus we aimed to investigate the efficacy and safety of monotherapy or combination therapy of adrenoceptor1 blockers and phosphodiesterase5 inhibitors for treatment. Randomized controlled trials up to November 2016 were retrieved from PubMed, the Cochrane Library, Web of Science and Embase. A total of 17 studies were included. We analyzed data through random or fixed effect models. The heterogeneity between studies was assessed by the I2 test statistic. As for lower ureter stones, our analysis demonstrated tadalafil had a significantly lower incidence of abnormal ejaculation than adrenoceptor1 blockers (2.31 95%CI 0.22to0.84, P = 0.01),while combination therapy had a higher expulsion rate (2.49 95%CI 1.44to4.29, P = 0.001) and shorter expulsion time (− 1.98 95%CI -3.08to0.88, P = 0.0004) than tamsulosin. As for lower urinary tract symptoms, our analysis indicated adrenoceptor1 blockers was more effective than phosphodiesterase5 inhibitors on decreasing International Prostate Symptom Score (1.96 95%CI 0.03to3.89, P = 0.05) and Post-Void Residual (9.41 95%CI 1.40to14.41, P = 0.02) and phosphodiesterase5 inhibitors showed a greater effect than adrenoceptor1 blockers on improving Erectile Dysfunction (2.23 95%CI 1.24to3.22, P<0.0001).Combination therapy had a significantly better effect on International Prostate Symptom Score (1.47 95%CI 1.25to1.69, P<0.0001), Maximum flow rate (0.87 95%CI 0.71to1.04, P<0.0001), Post-Void Residual (10.74 95%CI 3.53to17.96,P = 0.004) and Quality of life (0.59 95%CI 0.22to0.97, P = 0.002) but was associated with higher incidences of adverse events (3.40 95%CI 1.82to6.36, P = 0.0001) than adrenoceptor1 blockers. Combination therapy had a significantly better effect on International Prostate Symptom Score (4.19 95%CI 3.34to5.04, P<0.0001), Maximum flow rate (1.86 95%CI 1.32to2.39, P<0.0001), Post-Void Residual (22.58 95%CI 9.13to36.04, P = 0.001) and Quality of life (0.68 95%CI 0.37to1.00, P<0.0001) without higher incidences of adverse events than PDE5-Is. In conclusion, this meta-analysis suggested combination therapy had a best efficacy of therapy for lower ureteric stones or lower urinary tract symptoms correlated with benign prostatic hyperplasia than monotherapy. Adrenoceptor1 blockers was more effective than phosphodiesterase5 inhibitors on International Prostate Symptom Score and Post-Void Residual. Both monotherapy and combination therapy were safe.