MiR-125b-5p suppresses the bladder cancer progression via targeting HK2 and suppressing PI3K/AKT pathway.
- 作者列表："Liu S","Chen Q","Wang Y
:Bladder cancer (BCa) is identified as the most common malignant solid cancer in the urogenital tract. Recently, dysregulation of miRNAs has received more attention because of its extensive role in the carcinogenesis of BCa. This research was designed to verify how miR-125b-5p be involved in BCa development. The expression of miR-125b-5p was detected in 52 pairs of BCa specimens and adjacent normal bladder specimens. The effects of miR-125b-5p on BCa viability, migration, and apoptosis in vitro were examined. We then examined directly target gene(s) of miR-125b-5p in BCa cells. Our data demonstrated that miR-125b-5p was decreased in BCa tissues and cell lines. Patients with low miR-125b-5p expression had obviously shorter 5-year survival time. Lower miR-125b-5p expression was significant correlated with distant metastasis, tumor size and lymph node metastasis. Ectopic expression of miR-125b-5p inhibited the BCa cell viability and migration and induced cell apoptosis. Furthermore, HK2 was confirmed regulated by miR-125b-5p. HK2 recovered miR-125b-5p-mediated suppression of BCa cell viability and migration. In addition, miR-125b-5p also exhibited suppressive effect on PI3K/AKT pathway. Overall, these data indicate that miR-125b-5p played a role in the suppressive effect on BCa by targeting HK2 through suppressing PI3K/AKT pathway and offer a potential therapeutic target for BCa.
: 膀胱癌 (BCa) 被确定为泌尿生殖道中最常见的恶性实体癌。近年来，由于mirna在BCa癌变过程中的广泛作用，其调控异常受到了越来越多的关注。本研究旨在验证miR-125b-5p如何参与BCa开发。在52对BCa标本和癌旁正常膀胱标本中检测到miR-125b-5p的表达。检测了miR-125b-5p对体外BCa活力、迁移和凋亡的影响。然后我们检测了BCa细胞中miR-125b-5p的直接靶基因。我们的数据证明在BCa组织和细胞系中miR-125b-5p降低。低miR-125b-5p表达的患者5年生存时间明显缩短。miR-125b-5p低表达与远处转移、肿瘤大小及淋巴结转移显著相关。miR-125b-5p的异位表达抑制BCa细胞活力和迁移，并诱导细胞凋亡。此外，HK2被确认受miR-125b-5p监管。HK2恢复了对BCa细胞活力和迁移的miR-125b-5p-mediated抑制。此外，miR-125b-5p还表现出对PI3K/AKT通路的抑制作用。总体而言，这些数据表明miR-125b-5p通过抑制PI3K/AKT途径靶向HK2而在对BCa的抑制作用中发挥作用，并为BCa提供潜在的治疗靶标。
METHODS:PURPOSE:Studies indicate that molecular subtypes in muscle invasive bladder cancer predict the clinical outcome. We evaluated whether subtyping by a simplified method and established classifications could predict the clinical outcome. MATERIALS AND METHODS:We subtyped institutional cohort 1 of 52 patients, including 39 with muscle invasive bladder cancer, an Oncomine™ data set of 151 with muscle invasive bladder cancer and TCGA (The Cancer Genome Atlas) data set of 402 with muscle invasive bladder cancer. Subtyping was done using simplified panels (MCG-1 and MCG-Ext) which included only transcripts common in published studies and were analyzed for predicting metastasis, and cancer specific, overall and recurrence-free survival. TCGA data set was further analyzed using the Lund taxonomy, the Bladder Cancer Molecular Taxonomy Group Consensus and TCGA 2017 mRNA subtype classifications. RESULTS:Muscle invasive bladder cancer specimens from cohort 1 and the Oncomine data set showed intratumor heterogeneity for transcript and protein expression. MCG-1 subtypes did not predict the outcome on univariate or Kaplan-Meier analysis. On multivariate analysis N stage (p ≤0.007), T stage (p ≤0.04), M stage (p=0.007) and/or patient age (p=0.01) predicted metastasis, cancer specific and overall survival, and/or the cisplatin based adjuvant chemotherapy response. In TCGA data set publications showed that subtypes risk stratified patients for overall survival. Consistently the MCG-1 and MCG-Ext subtypes were associated with overall but not recurrence-free survival on univariate and Kaplan-Meier analyses. TCGA data set included 21 low grade specimens of the total of 402 and subtypes associated with tumor grade (p=0.005). However, less than 1% of muscle invasive bladder cancer cases are low grade. In only high grade specimens the MCG-1 and MCG-Ext subtypes could not predict overall survival. On univariate analysis subtypes according to the Bladder Cancer Molecular Taxonomy Group Consensus, TCGA 2017 and the Lund taxonomy were associated with tumor grade (p <0.0001) and overall survival (p=0.01 to <0.0001). Regardless of classification, subtypes had about 50% to 60% sensitivity and specificity to predict overall and recurrence-free survival. On multivariate analyses N stage and lymphovascular invasion consistently predicted recurrence-free and overall survival (p=0.039 and 0.003, respectively). CONCLUSIONS:Molecular subtypes reflect bladder tumor heterogeneity and are associated with tumor grade. In multiple cohorts and subtyping classifications the clinical parameters outperformed subtypes for predicting the outcome.
METHODS::Acquired chemoresistance is a critical issue for advanced bladder cancer patients during long-term treatment. Recent studies reveal that a fraction of tumor cells with enhanced tumor-initiating potential, or cancer stem-like cells (CSCs), may particularly contribute to acquired chemoresistance and recurrence. Thus, CSC characterization will be the first step towards understanding the mechanisms underlying advanced disease. Here we generated long-term patient-derived cancer cells (PDCs) from bladder cancer patient specimens in spheroid culture, which is favorable for CSC enrichment. Pathological features of bladder cancer PDCs and PDC-dependent patient-derived xenografts (PDXs) were basically similar to those of their corresponding patients' specimens. Notably, CSC marker aldehyde dehydrogenase 1A1 (ALDH1A1), a critical enzyme that synthesizes retinoic acid (RA), was abundantly expressed in PDCs. ALDH1A1 inhibitors and shRNAs repressed both PDC proliferation and spheroid formation, whereas all-trans RA could rescue ALDH1A1 shRNA-suppressed spheroid formation. ALDH inhibitor also reduced the in vivo growth of PDC-derived xenografts. ALDH1A1 knockdown study showed that tubulin beta III (TUBB3) was one of the downregulated genes in PDCs. We identified functional RA response elements in TUBB3 promoter, whose transcriptional activities were substantially activated by RA. Clinical survival database reveals that TUBB3 expression may associate with poor prognosis in bladder cancer patients. Moreover, TUBB3 knockdown was sufficient to suppress PDC proliferation and spheroid formation. Taken together, our results indicate that ALDH1A1 and its putative downstream target TUBB3 are overexpressed in bladder cancer, and those molecules could be applied to alternative diagnostic and therapeutic options for advanced disease.
METHODS:OBJECTIVES:To evaluate the technical feasibility, oncological and functional outcomes of nerve sparing cystoprostatectomy (NSCP) and prostate capsule-sparing cystectomy (PCSC) for the treatment of organ-confined bladder cancer at a single referral centre. PATIENTS AND METHODS:From April 2001 to June 2012, 60 patients underwent PCSC and 47 were treated with NSCP. Inclusion criteria for PCSC were: fully informed consent for the well-motivated patient; negative transurethral resection of the bladder neck; normal prostatic specific antigen (PSA) level (defined as <4 ng/dL during the first year of the study, which was later lowered to 2.5 ng/dL); and normal transrectal ultrasonography, with biopsy for any suspicious nodule. Patients received a complete oncological and functional follow-up. The Kaplan-Meier method was used to depict survival outcomes after surgery. RESULTS:After a median follow-up of 73 and 62 months for PCSC and NSCP, respectively, the 5-year cancer-specific survival was 90% for the PCSC group and 78% for the NSCP group (P = 0.055). Considering complications within 30 days after surgery, 13% and 21% patients had Clavien ≥III complications in the PCSC and NSCP groups, respectively (P = 0.2). For functional outcomes, at 3 months after surgery, 54 (90%) and 24 (51%) patients reported full recovery of daytime urinary continence in the PCSC and NSCP groups, respectively (P < 0.001); and for erectile function recovery, 32 (53%) and four (9%) patients in the PCSC group and in the NSCP group were respectively potent without any treatment (P < 0.001). CONCLUSIONS:NSCP and PCSC are appropriate for a subset of patients with bladder cancer, with excellent oncological and functional results. These surgical procedures should be proposed to well-motivated patients.