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  • br Research in context br Evidence before this study br

    2020-08-30


    Research in context
    Evidence before this study
    Cancer stem-like cells (CSCs) have been implicated in drug resis-tance and disease progression of prostate cancer, which is the first most frequently diagnosed malignancies and the second lead-ing cause of cancer-related deaths among men in developed coun-tries. We previously reported that cell division cycle 20 (CDC20) was up-regulated in high Gleason score tissues of prostate cancer, and CDC20 exerts its carcinogenic function in many malignancies mainly during the metaphase to Wortmannin by disrupting key cell cycle regulators.
    Added value of this study
    Our study showed that CDC20 maintains the self-renewal ability of CD44+ prostate CSCs by promoting nuclear translocation and trans-activation of β-catenin. In addition, CDC20 combined with CD44 or β-catenin can serve as an important indicator for progno-sis of patients with prostate cancer.
    Implications of all the available evidence
    Our findings shared new insights into the relationship between CDC20 and stem-like features of CSCs during tumorigenesis in prostate cancer, suggesting inhibition of CDC20 may prevent or slow prostate cancer progression by inactivating CSCs subset.
    Therefore, targeting prostate CSCs to make them sensitive to chemo-therapy can be used as a novel therapeutic paradigm for metastatic CRPC patients.
    In our previous study, we identified five hub genes associated with poorly differentiated prostate cancer, including cell division cycle 20 (CDC20) [20], a regulator of cell cycle checkpoints which activates ade-nomatous polyposis coli (APC) [21]. CDC20 is a key E3 ligase, a protein containing the WD40 repeat domain that binds to APC and recognises D-box or KEN box substrates to promote proteasomal degradation. APC/CDC20 exerts its carcinogenic function during the metaphase to anaphase by disrupting key cell cycle regulators [22]. Abnormal levels or dysfunction of CDC20 can abolish mitotic arrest, thereby promoting premature lateness by relaxing APC activation, leading to aneuploidy in daughter cells [23]. Interestingly, increased CDC20 expression has been reported to be associated with poor pathological features and poor prognosis in many human cancer types [24–26]. In addition, previ-ous studies showed that CDC20 regulates hematopoiesis and leukemia in hematopoietic stem cells by promoting ubiquitination of MEIS1 and p21, and maintains the self-renewal potential of human glioblastoma by regulating SOX2 protein and promoting SOX2-dependent transcrip-tion [27]. However, the expression and role of CDC20 in prostate CSCs remains poorly understood.
    In this study, the functional role of CDC20 in maintaining the stem like characteristics of prostate CSCs was assessed. Our founding indi-cated that CDC20 was preferentially enriched in prostate CSC and asso-ciated with poor prognosis in prostate cancer patients. Simultaneously, the interference of CDC20 resulted in the reduction of prostate CSCs by inhibiting their self-renewal, drug resistance, invasion capability and tu-morigenicity. In addition, our results suggested that CDC20 exerts a key role in maintaining the stem-like properties of CD44+ CSCs in prostate cancer by promoting nuclear translocation and transactivation of β-catenin. Thus, our findings shared new insights into the relationship be-tween CDC20 and stem-like features of CSC during tumorigenesis. 
    Therefore, inhibition of CDC20 may be utilized to inhibit prostate cancer progression by inactivating CSC subset.
    2. Materials and methods
    2.1. Patients and specimens
    We followed the reporting recommendations for tumour marker prognostic studies (REMARK) in this study [28]. Clinical data, tissue specimens and follow-up information were collected for 121 consecu-tive prostate cancer patients who were pathologically diagnosed and re-ceived prostatectomy between 2012 and 2013, and 8 prostate cancer patients who received prostate needle biopsy after docetaxel treatment. The clinical data of 121 prostate cancer patients included age at diagno-sis, preoperative PSA (the maximum within 6 months before the oper-ation), the postoperative pathological status including Gleason score (GS), pathological T stage, surgical margins (SM). Localised PCa refers to T1-T2, and locally advanced PCa (LAPC) refers to the patients with T stage ≥ T3 (Tumour extends through the prostatic capsule) according to the 2018th guideline of European Association of Urology. The time to biochemical recurrence (BCR) (cutoff: PSA = 0.2 ng/mL) and disease progression identified by MRI, CT or ECT were selected as the clinical endpoint of biochemical relapse free survival and disease-free survival, respectively. Hematoxylin and eosin (H&E)-stained sections of the pros-tate cancer specimens were re-evaluated by two experienced patholo-gists (Jun-hui Ge and Xi-quan Yang) to identify representative areas in double blind procedure. Tumour stage and GS were assessed according to the American Joint Committee on Cancer (AJCC) 2002 and the inter-national society of urological pathology (ISUP) consensus conference 2014 [29]. The samples were obtained after writing informed consent from patients according to an established protocol approved by the Ethics Committee of Second Military Medical University. The clinical features are summarized in Supplementary Table S1.