Feedback activation of GATA1/miR-885-5p/PLIN3 pathway decreases sunitinib sensitivity in clear cell renal cell carcinoma.

Sunitinib is the most commonly used first-line therapy for the treatment of advanced renal cell carcinoma (RCC), but intrinsic and extrinsic resistance to targeted therapies dramatically compromise the benefit of clinical outcome. Dissecting the underlying mechanisms and discovering reliable predictive biomarkers are urgently needed in clinic. Here, we discovered miR-885-5p was notably decreased after sunitinib treatment and associated with poor disease progression in clear cell renal cell carcinoma (ccRCC). In vitro and in vivo studies identified miR-885-5p inhibition contributed to sunitinib resistance. Mechanistically, sunitinib treatment reduced GATA1 expression, which in turn reduced its binding to MIR885 promoter and resulted in miR-885-5p downregulation in transcriptional level. In addition, PLIN3 was confirmed to be directly targeted by miR-885-5p and its upregulation significantly increased lipid droplets formation to decrease sunitinib sensitivity. Therefore, GATA1/miR-885-5p/ PLIN3 pathway may serve as a potential therapeutic strategy and a biomarker for sunitinib treatment in ccRCC.

Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis.

Neuroblastoma (NB) is the most common extracranial tumor in children. Unlike in most adult tumors, tumor suppressor protein 53 (p53) mutations occur with a relatively low frequency in NB and the downstream function of p53 is intact in NB cell lines. Wip1 is a negative regulator of p53 and hindrance of Wip1 activity by novel inhibitor GSK2830371 is a potential strategy to activate p53's tumor suppressing function in NB. Yet, the in vivo efficacy and the possible mechanisms of GSK2830371 in NB have not yet been elucidated. Here we report that novel Wip1 inhibitor GSK2830371 induced Chk2/p53-mediated apoptosis in NB cells in a p53-dependent manner. In addition, GSK2830371 suppressed the colony-formation potential of p53 wild-type NB cell lines. Furthermore, GSK2830371 enhanced doxorubicin- (Dox) and etoposide- (VP-16) induced cytotoxicity in a subset of NB cell lines, including the chemoresistant LA-N-6 cell line. More importantly, GSK2830371 significantly inhibited tumor growth in an orthotopic xenograft NB mouse model by inducing Chk2/p53-mediated apoptosis in vivo. Taken together, this study suggests that GSK2830371 induces Chk2/p53-mediated apoptosis both in vitro and in vivo in a p53 dependent manner.

Evaluation of the improved tubeless cutaneous ureterostomy technique following radical cystectomy in cases of invasive bladder cancer complicated by peritoneal metastasis.

Radical cystectomy, as the most common surgical treatment for patients with invasive bladder cancer (IBC) complicated by peritoneal metastasis, is usually accompanied by a urinary diversion procedure. In this study, we evaluated the improved tubeless cutaneous ureterostomy technique by comparing the resulting clinical effects with either a traditional ureterostomy and an ileal conduit urinary diversion. Clinical data from 85 patients who underwent 1 of the 3 procedures between April 2012 and April 2015 were analyzed retrospectively. In total, 30 patients underwent improved tubeless cutaneous ureterostomy, 28 patients underwent a traditional cutaneous ureterostomy and 27 underwent an ileal conduit urinary diversion following radical cystectomy. The incidence of complications, including stoma infection, nipple atrophy, terminal necrosis, urine leakage, external orifice stenosis, uronephrosis and ureterectasia in the group of patients treated with the improved tubeless ureterostomy technique was significantly lower than that of the patients in the other 2 groups, and the difference was statistically significant (P<0.05). In addition, the duration of the surgery, intra-operative bleeding, the duration of the hospitalization period and the time to extubation in the patients treated with the improved tubeless ureterostomy technique were significantly decreased (P<0.05) compared with the patients in the other 2 groups. Finally, the health-related quality of life of the patients treated with the improved tubeless ureterostomy technique was significantly higher (P<0.05) than that of the patients in the other 2 groups. The findings of our study demonstrated that the use of the improved tubeless cutaneous ureterostomy technique following radical cystectomy in patients with IBC complicated by peritoneal metastasis resulted in improved clinical effects. Thus, improved tubeless cutaneous ureterostomy may be a promising alternative for enhancing the quality of life of patients with IBC.