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  • br Results and Discussion br Materials and Methods br Acknow


    Results and Discussion
    Materials and Methods
    Introduction Among the solid tumors, Prostate cancer (PCa) has been one of the most frequently diagnosed malignancy in men and the second male's cancer related deaths in the developed countries [1]. In China, the incidence and mortality of PCa are increasing in recent years [2, 3]. Radical prostatectomy (RP) provides excellent outcomes for most of the localized PCa [4, 5]; however, up to 25% of the post-RP cases may be very aggressive and cancer reappears after surgery. Biochemical recurrence (BCR), i.e., the post-RP PSA level bounces back over 2 ng/ml, is a commonly used standard for monitoring PCa relapse [6]. To address the long-lasting problem of overtreatment in PCa, effective prognostic markers are needed to distinguish the aggressive cases from the indolent cases. Using clinical and histological features/markers for management of the disease, such as personalized treatment plan, is the clinic standard. Molecular markers have been sought to improve the prognostic accuracy, and some gene panels have been translated to clinical application [7, 8]. In this study, we explore the potential clinical relevance of a novel gene, i.e., dCTP pyrophosphatase 1 (DCTPP1), to PCa progression. DCTPP1 is one of the member in Nucleoside triphosphate pyrophosphohydrolases (NTP-PPase) which has been recently reported as the potential target of anticancer drugs [[9], [10], [11], [12], [13]]. It is known as a housekeeper for deoxynucleotide triphosphate (dNTP) pool balance, and its main biological function is to maintain the accuracy of DNA replication by cleaving harmful nucleotides [[14], [15], [16]]. Overexpression of DCTPP1 has been linked to poor prognosis in multiple cancers [17]. DCTPP1 was also found to promote the stemness in breast cancer INF39 and increase chemo-resistance in gastric cancer [18, 19]. Nevertheless, whether DCTPP1 plays any roles in prostate cancer has not been addressed in literatures. DCTPP1 came on our radar because of its relatedness with two important PCa relevant genes, i.e., Pten and Atg7. Pten is a well-known tumor suppress gene which is often found to be mutated in various types of cancers [20, 21]. Urmila Santanam et al. reported that Atg7 deficiency delays prostate cancer progression in Pten loss genetically engineered mouse model [22]. Interestingly, ATG7, known to function as an ubiquitin-like protein, plays a crucial role in the autophagy related pathways. Macroautophagy, or autophagy, is a physiological process that deals with destruction of cells or cellular components in an organism. Double-membraned vesicles, called autophagosomes, are formed to isolate and degrade targeted cytoplasmic constituents with fused lysosomes [23]. In a normal cell, autophagy robustly inhibits malignant transformation, such as inhibition of onco-proteins and activation of onco-suppressor proteins [24], and contributes to natural and therapy-driven anticancer immunosurveillance [25]. However, owing to its cell-intrinsic effects, autophagy supports the progression of established neoplasms as well as their resistance to conventional treatments [[26], [27], [28], [29], [30]]. By scrutinizing The Cancer Genome Atlas (TCGA) RNA-seq datasets of PCa, we found DCTPP1 was significantly correlated with Pten and Atg7. We hypothesize that DCTPP1 may affect the PCa phenotypes by being involved in autophagy activities in PCa cells. To test this hypothesis, we analyzed the expression of DCTPP1 in human PCa tissues versus non-cancerous prostate tissues. The potential roles of DCTPP1 associated with autophagy activities and tumor progression were tested using in vitro and in vivo experiments, and further verified with a series of bioinformatics assays.
    Materials and methods
    Discussion Molecular markers have been clinically applied to the management of PCa, for example, Prolaris (46-gene test) from Myriad Genetics Inc., 22-gene test from Decipher Inc., and Genomic Prostate Score (17-gene test) from Oncotype DX. New markers are being sought and added to the existing panels to improve their diagnostic and prognostic performances [39]. In the current study, we focused on a new potential prognostic marker DCTPP1, a member in Nucleoside triphosphate pyrophosphohydrolases, and explored its clinical potential in predicting outcomes of PCa patients.