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  • In the PTEN loss mouse model deletion of ATG


    In the PTEN loss mouse model, deletion of ATG7 gene not only caused an autophagy-deficient phenotype, but also postponed the progression of inoculated prostate tumor [22]. On the basis of these experimental facts, these ATG7 and PTEN related genes were then compared with the 3020 BCR-associated genes which were uncovered by univariate survival analysis, yielding 61 common genes including DCTPP1 (see Venn Diagram). In cell division, there is about one error in every 107 replicated DNA bases per generation; these damages need to be identified and corrected through repair mechanisms in NKY 80 [15]. DCTPP1, which is distributed in the nucleus, cytosol and mitochondria, plays a critical role in the DNA repair mechanisms by eliminating excess dCTP after DNA synthesis for the stabilization of dNTP pools and preventing overmethylation of CpG islands [9]. Increased expression of DCTPP1 has been reported to be associated with poor clinical outcomes in various cancers, including lung cancer, breast cancer, liver cancer, cervical cancer, gastric cancer and esophagus cancer [17]. Moreover, Song et al. indicated that DCTPP1 acts as an intracellular modulator for 5-methyl-dCTP metabolism and global hypomethylation, promoting cancer cell proliferation and stemness properties in breast cancer [18]. Xia et al. suggested that DCTPP1 is responsible for chemoresistance in gastric cancer because of DCTPP1-induced hypomethylation of MDR1 promoter region which results in an increased expression of MDR1 in tumor cells. Moreover, NTPPPases has been reported as a potential cancer therapeutic target in an increasing number of publications [19]. However, whether DCTPP1 also plays an important role in PCa remains unclear, and to answer this question becomes the focus of the current study. The analysis of TCGA dataset indicated that increased expression of DCTPP1 was associated unfavorable outcomes of prostate cancer. These observations are consistent with our results of immunohistochemistry analysis too. When Gleason scores of 8 and 9 were used as cutoffs, the differences between two groups (low Gleason vs. high Gleason) were highly significant with P values < 0.001. However, when Gleason score of 7 was used as cutoff, the result was not significant but the same trend has been observed. A close look at the standard deviations associated with the groups defined using various cutoffs indicated that expression level of DCTPP1 is more homogeneous or less variable in high Gleason groups (≥8 or ≥9) than in low Gleason group (<7). The non-significant result using Gleason score of 7 as cutoff may be due to the fact that only 22 patients with heterogeneous expression of DCTPP1 are in the low Gleason group and there is little statistical power to detect the difference between two groups (low Gleason vs. high Gleason). A study with larger sample size is needed to make a definitive conclusion for DCTPP1 when Gleason score of 7 is considered as a cutoff value. Further in vitro or in vivo experiments showed that overexpression of DCTPP1 promoted cell invasion, migration, proliferation, EMT and inhibited apoptosis. The functional relationship between DCTPP1 with ATG7 and PTEN, and the role that DCTPP1 plays to impact the phenotype of prostate tumor becomes interesting. ATG7 is a key gene in autophagy because it encodes E1-like activating enzyme which is required for vacuole transporting. As one of the most importance cellular mechanisms for the maintenance of a healthy cell and its homeostasis, autophagy functions as a scavenger to remove unnecessary or dysfunctional components, waste, and harmful substances [40]. This feature of autophagy in normal cells well explains why it is one of the defensive barriers preventing transformation to cancerous cells. It has been reported that implementation of anticancer immunosurveillance, inhibition of oncoproteins, and enhancement of oncosuppressor proteins rely on autophagy [14]. The autophagy activity substantially dropped in precancerous cells, facilitating malignant transformation [27]. In cancerous cells where malignant transformation has been completed, the previously suppressed autophagy is restored or even enhanced and starts eliminating cellular substances that are ‘harmful’ to the tumorous cells, leading to resistance to therapies and thereafter promoting tumor progression [41]. For example, autophagy can counterbalance the damage of hypoxia and nutrient deprivation, enhance the resistance of chemotherapy, and maintain the stemness in the cancer cells [26, 27]. Lazova R et al. found that autophagy promoted proliferation, invasion and metastasis, and the level of autophagy activity was correlated with nuclear grade and outcomes of melanoma and breast tumors [42]. Mikhaylova O et al. reported that miR-204 postponed tumor progression by suppressing LC3B-mediated autophagy in renal carcinomas cells [43]. In addition, a number of publications showed that some autophagy inhibitors revealed a certain antineoplastic effects on confirmed tumors, particularly combine with other therapies [44, 45].