Acetyl-CoA carboxylase 1 depletion suppresses de novo fatty acid synthesis and mitochondrial ß-oxidation in castration-resistant prostate cancer cells.

Cancer cells, including those of prostate cancer (PCa), often hijack intrinsic cell signaling to reprogram their metabolism. Part of this reprogramming includes the activation of de novo synthesis of fatty acids that not only serve as building blocks for membrane synthesis but also as energy sources for cell proliferation. However, how de novo fatty acid synthesis contributes to PCa progression is still poorly understood. Herein, by mining public datasets, we discovered that the expression of acetyl-CoA carboxylase alpha (ACACA), which encodes acetyl-CoA carboxylase 1 (ACC1), was highly expressed in human PCa. In addition, patients with high ACACA expression had a short disease-free survival time. We also reported that depletion of ACACA reduced de novo fatty acid synthesis and PI3K/AKT signaling in the human castration-resistant PCa (CRPC) cell lines DU145 and PC3. Furthermore, depletion of ACACA downregulates mitochondrial beta-oxidation, resulting in mitochondrial dysfunction, a reduction in ATP production, an imbalanced NADP+/NADPhydrogen(H) ratio, increased reactive oxygen species, and therefore apoptosis. Reduced exogenous fatty acids by depleting lipid or lowering serum supplementation exacerbated both shRNA depletion and pharmacological inhibition of ACACA-induced apoptosis in vitro. Collectively, our results suggest that inhibition of ectopic ACACA, together with suppression of exogenous fatty acid uptake, can be a novel strategy for treating currently incurable CRPC.

Arginase 2 is a Diagnostic and Prognostic Marker for Prostate Cancer and Is Associated with Metabolism.

Objective: Metabolism, a basic need and biochemical process for cell survival and proliferation, is closely connected with the pathogenesis and progression of prostate cancer. Methods: A four-gene signature construct that includes CKM (CKM), CD38, Enoyl Coenzyme A(EHHADH), and Arginase 2(ARG2) was created by bioinformatics. Finally, hub genes were validated by IHC and in vitro experiments. Results: The results showed the AUCs of the logistic regression and neural networks diagnostic model for the diagnosis of two subtypes were 0.920 and 0.936, respectively. The risk score demonstrated by univariable and multivariable Cox analysis is an independent predictive component of the prognostic signature for DFS. According to immunohistochemical analyses, ARG2 and CD38 expression levels were considerably under-expressed, but CKM and EHHADH expression levels were significantly overexpressed. Furthermore, The expression of ARG2 was significantly down-regulated in the late Gleason score. Finally, we found that ARG2 is lowly expressed in prostate cancer cells. Furthermore, based on the effect of ARG2 on the malignant phenotype of PCa in vitro, we also found that ARG2 may be a tumor suppressor that plays an important role in inhibiting proliferation, migration, and invasion. Conclusions: These findings suggest that ARG2 has been tentatively identified as a new target for research into how PCa develops in metabolism and for the development of innovative targeted treatments.

DCUN1D1 promotes tumour progress in prostate cancer and its effect on DU145 in vitro.

OBJECTIVE: To compare the expression levels of Defective In Cullin Neddylation 1 Domain Containing 1 oncogene in prostate cancer tissues and normal prostate tissues, to explore its effect on cancerous cells, and to investigate its underlying mechanisms on such cells in vitro. METHODS: The cross-sectional study was conducted at Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics from Jan 03,2017 to Nov 05,2018, and comprised prostate tissue samples on which immunohistochemistry was used to detect the expression of Defective In Cullin Neddylation 1 Domain Containing 1 oncogene. Short hairpin ribonucleic acid expression plasmid targeting the oncogene was constructed and transferred into prostate cance cell line DU145. The roles of the oncogene in prostate cancer progression were confirmed in vitro. The expression of vimentin and epithelial cadherin influenced by the oncogene were detected using Western blot. Data was analysed using SPSS 24. RESULTS: Of the 80 samples, 3(3.75%) were normal prostate tissues, 7(8.75%) adjacent normal prostate tissues, 20(25%) hyperplasia, and 50(62.5%) prostate cancer tissues. Defective In Cullin Neddylation 1 Domain Containing 1 oncogene expression in prostate cancerous tissues was significantly associated with high Gleason score (p<0.001), metastasis (p<0.05) and pathological stage (p<0.001). The oncogene was found to be an independent prognostic factor for disease-free survival of prostate cancer patients (p=0.0108). In vitro analysis confirmed the tumour promotive role of the oncogene through cell proliferation, invasion and migration assays. Its expression was closely correlated with aggressive progression and poor prognosis in prostate cancer patients (p<0.05). Vimentin and epithelial cadherin were affected by the oncogene. CONCLUSIONS: Defective In Cullin Neddylation 1 Domain Containing 1 oncogene highly expressed in DU145 and the prostate cancer tissues, which correlated with prognosis.

Overexpression of SLC6A1 associates with drug resistance and poor prognosis in prostate cancer.

BACKGROUND: Solute Carrier Family 6 Member 1 (SLC6A1) has been identified as a cancer-promoting gene in various human cancers, such as clear cell renal cell carcinoma and ovarian cancer. However, its roles in prostate cancer (PCa) has not been fully elucidated. The aim of this study was to investigate the expression and clinical significance of SLC6A1 in PCa tissues and its effect on drug resistance to docetaxel in PCa. METHODS: Expression patterns of SLC6A1 protein in PCa tissues were examined by immunohistochemistry based on Tissue microarray. Associations of SLC6A1 protein expression with various clinicopathological features and patients' prognosis of PCa were also statistically evaluated based on TCGA data. Roles of SLC6A1 deregulation in prostate carcinogenesis and drug resistance was further determined in vitro and in vivo experiments. RESULTS: Based on TCGA Dataset, SLC6A1 expression was markedly higher in patients with high Gleason score, advanced clinical stage and positive biochemical recurrence than those with control features (all P < 0.05). Both unvariate and multivariate analyses demonstrated that SLC6A1 expression was significantly associated with biochemical recurrence-free survival in PCa patients. In addition, enforced expression of SLC6A1 effectively promoted cell proliferation, migration and invasion of PCa cells in vitro. Moreover, the inhibition of SLC6A1 suppressed the tumor growth in vivo. Additionally, immunohistochemical notches of PCNA and MMP-9 in the low-expression cluster were pointedly lower compared to those of NC group. Finally, the cell viability revealed that the overexpression of SLC6A1 obviously promoted the PCa cell resistant to docetaxel (DTX), and the transplanted tumor in the overexpression group had no significant reduction compared with the untreated group. CONCLUSIONS: Our data suggest that SLC6A1 overexpression may be associated with aggressive progression and short biochemical recurrence-free survival of PCa, and may be related to the resistance to docetaxel therapy.

KIF4A: A potential biomarker for prediction and prognostic of prostate cancer.

PURPOSE: To investigate the clinical relevance and biological function of the kinesin super-family protein 4A (KIF4A) expression in prostate cancer (PCa). METHODS: We examined 1) the relationship between the expression of KIF4A and clinico-pathological characteristics of PCa patients using a tissue microarray and the Cancer Genome Atlas database, 2) the prognostic value of KIF4A expression in patients using Kaplan-Meier plots and 3) the functions of KIF4A in LNCaP and DU145 cells, such as cell proliferation, cell cycle and cell apoptosis. RESULTS: Compared with normal prostate, the mRNA and protein expressions of KIF4A were up-regulated in PCa. The up-regulation expression rates of KIF4A in PCa were significantly related to the Gleason score (P.

Correction to: MicroRNA-30d promotes angiogenesis and tumor growth via MYPT1/c-JUN/VEGFA pathway and predicts aggressive outcome in prostate cancer.

After publication of the article [1], the author reported that this article contained some errors.

Expression of PD-L1 in tumor-associated nerves correlates with reduced CD8+ tumor-associated lymphocytes and poor prognosis in prostate cancer.

To investigate immune profile consisting of stromal PD-L1 expression, inhibitory or non-T-cell inflamed tumor microenvironment that may predict response to anti-PD-L1/PD-1 immunotherapy in prostate cancer, we validated the specificity of a PD-L1 monoclonal antibody (E1L3N) and identified PD-L1 specific expression in prostatic stromal nerve cells. PD-L1 expression was analyzed in 73 primary prostate cancers and 7 castration-resistant prostate cancers (CRPC) by immunohistochemistry (IHC) and resulting data from primary prostate cancers were correlated with tumor-associated lymphocytes (TALs), clinicopathological characteristics and clinical outcome. PD-L1 was expressed in the tumor cells in only one primary prostate cancer case and none of the CRPC. However, PD-L1 was frequently observed in the nerve branches in the tumor-associated stroma (69 of 73 cases, 94.5%), supported by colocalization with axonal marker PGP9.5. FoxP3-, CD3- and CD8-positive T lymphocytes were observed in 74.6% (47/63), 98.4% (62/63) and 100% (61/61) of the cases, respectively. The density of PD-L1+ tumor-associated nerves (TANs) was inversely correlated with that of CD8+ TALs. Higher density of PD-L1+ TANs was significantly associated with biochemical recurrence (BCR) in Kaplan-Meier survival analysis (p = 0.016). In both univariate and multivariate Cox analysis, the density of PD-L1+ TANs was independently prognostic of BCR. In conclusion, PD-L1 expression is rare in prostate tumor cells but prevalent in TANs and negatively correlated with CD8+ TALs. Neuro-immunological interaction may be a contribution to immune-suppressive microenvironment. Combinatorial treatment regimen designs to neural PD-L1 and TALs should be warranted in future clinical application of anti-PD-L1/PD-1 immunotherapy in prostate cancer.

Proposal of a Nomogram for Predicting Survival in Patients with Siewert Type II Adenocarcinoma of the Esophagogastric Junction After Preoperative Radiation.

BACKGROUND: Preoperative radiotherapy tends to be more frequently used for patients with adenocarcinoma of the esophagogastric junction (AEG); however, the prognostic values of postoperative pathologic characteristics in these patients remain unclear. This study aimed to examine the outcomes in Siewert type II AEG patients receiving preoperative radiotherapy to identify the predictive factors for overall survival (OS). METHODS AND RESULTS: A total of 1818 AEG patients undergoing preoperative radiotherapy were reviewed. Univariate analyses showed that age, sex, histology, tumor grade, positive lymph node (PLN), lymph node ratio, and log odds of positive lymph nodes (LODDS) were significantly correlated with OS; however, only age, grade, PLN, and LODDS were identified as independent risk factors in a multivariate regression model. Subsequently, patients were randomly grouped into training and validation cohorts (1:1 ratio), and the beta coefficients of these variables in the training set were used to generate the nomogram. The composite nomogram showed improved prognostic accuracy in the training, validation, and entire cohorts compared with that of TNM stage alone. CONCLUSIONS: In conclusion, our proposed nomogram represents a promising tool for estimating OS in Siewert type II AEG patients after preoperative radiotherapy.

Metastatic prostate cancer-associated P62 inhibits autophagy flux and promotes epithelial to mesenchymal transition by sustaining the level of HDAC6.

BACKGROUND: P62 (also named sequestosome-1, SQSTM1) is involved in autophagy regulation through multiple pathways. It interacts with autophagosomes-associated LC3-II and ubiquitinated protein aggregates to engulf the aggregates in autophagosomes, interacts with HDAC6 to inhibit its deacetylase activity to maintain the levels of acetylated α-tubulin and stabilities of microtubules to enhance autophagosome trafficking, and regulates autophagy initiation and cell survival. We performed immunohistochemistry staining of P62 in prostate tissues from prostate cancer patients and found that levels of P62 in patients with prostate adenocarcinomas (PCA) are significantly higher than those in patients with benign prostate hyperplasia (BPH). High levels of P62 predict high tumor grade and high intensity of metastasis. METHODS: We created prostate cancer cell lines stably overexpressing P62 and then suppress the expression of P62 in the cell line stably overexpressing P62 with CRISPR technology. Cell proliferation assay with crystal violet, cell migration assay, cell invasion assay, Western blot analysis, and confocal fluorescent microscopy were conducted to test the impact of altered levels of P62 on the growth, migration, invasion, epithelial-to-mesenchymal transition, autophagy flux, HDAC6 activity, and microtubular acetylation of cancer cells. RESULTS: P62 increased the levels of HDAC6 and reduced the acetylation of α-tubulin and the stability of microtubules. Consequently, high levels of P62 caused a promotion of epithelial-to-mesenchymal transition in addition to an impairment of autophagy flux, and further led to an enhancement of proliferation, migration, and invasion of prostate cancer cells. CONCLUSION: P62 promotes metastasis of PCA by sustaining the level of HDAC6 to inhibit autophagy and promote epithelial-to-mesenchymal transition.

BACH1 promotes the progression of human colorectal cancer through BACH1/CXCR4 pathway.

The present study was to investigate clinical significance, biological functions and underlying mechanisms of BTB Domain and CNC Homolog 1(BACH1) deregulation in human colorectal cancer (CRC). The result showed that BACH1 upregulation was significantly associated with enhanced tumor invasion (P = 0.014) and gender (P = 0.028) of CRC patients. Kaplan-Meier method results showed that the overall survival of CRC patients with high BACH1 mRNA expression was markedly shorter than those with low expression (P = 0.015), and multivariate analyzes results showed that BACH1 was an independent prognostic predictor for CRC patients (P = 0.049). In vitro studies revealed that BACH1 efficiently promoted invasion and migration of CRC cell line. In vitro studies proved that the HCT116 cell stably expressing BACH1 formed significantly larger tumor nodules and remarkably accelerated tumor xenografts growth. In addition, Immunohistochemical scores of CD31 and Vimentin were significantly higher than those of the control group. Finally, correlation analysis indicated that BACH1 expression was positively correlated with C-X-C Motif Chemokine Receptor 4(CXCR4) in tumor tissues and cell lines. Together, BACH1 serves as an oncogene to promote CRC progression and an independent prognostic factor for survival and metastasis. BACH1 may inhibit the progression of CRC through BACH1/CXCR4 pathway.

MicroRNA-30d promotes angiogenesis and tumor growth via MYPT1/c-JUN/VEGFA pathway and predicts aggressive outcome in prostate cancer.

BACKGROUND: Even though aberrant expression of microRNA (miR)-30d has been reported in prostate cancer (PCa), its associations with cancer progression remain contradictory. The aim of this study was to investigate clinical significance, biological functions and underlying mechanisms of miR-30d deregulation in PCa. METHODS: Involvement of miR-30d deregulation in malignant phenotypes of PCa was demonstrated by clinical sample evaluation, and in vitro and in vivo experiments. The mechanisms underlying its regulatory effect on tumor angiogenesis were determined. RESULTS: miR-30d over-expression was observed in both PCa cells and clinical specimens. High-miR-30d was distinctly associated with high pre-operative PSA and Gleason score, advanced clinical and pathological stages, positive metastasis and biochemical recurrence (BCR), and reduced overall survival of PCa patients. Through gain- and loss-of-function experiments, we found that miR-30d promoted PCa cell proliferation, migration, invasion, and capillary tube formation of endothelial cells, as well as in vivo tumor growth and angiogenesis in a mouse model. Simulation of myosin phosphatase targeting subunit 1 (MYPT1), acting as a direct target of miR-30d, antagonized the effects induced by miR-30d up-regulation in PCa cells. Notably, miR-30d/MYPT1 combination was identified as an independent factor to predict BCR of PCa patients. Furthermore, miR-30d exerted its pro-angiogenesis function, at least in part, by inhibiting MYPT1, which in turn, increased phosphorylation levels of c-JUN and activated VEGFA-induced signaling cascade in endothelial cells. CONCLUSIONS: miR-30d and/or its target gene MYPT1 may serve as novel prognostic markers of PCa. miR-30d promotes tumor angiogenesis of PCa through MYPT1/c-JUN/VEGFA pathway.

Role of GPR30 in estrogen-induced prostate epithelial apoptosis and benign prostatic hyperplasia.

Several studies have implicated estrogen and the estrogen receptor (ER) in the pathogenesis of benign prostatic hyperplasia (BPH); however, the mechanism underlying this effect remains elusive. In the present study, we demonstrated that estrogen (17ß-estradiol, or E2)-induced activation of the G protein-coupled receptor 30 (GPR30) triggered Ca2+ release from the endoplasmic reticulum, increased the mitochondrial Ca2+ concentration, and thus induced prostate epithelial cell (PEC) apoptosis. Both E2 and the GPR30-specific agonist G1 induced a transient intracellular Ca2+ release in PECs via the phospholipase C (PLC)-inositol 1, 4, 5-triphosphate (IP3) pathway, and this was abolished by treatment with the GPR30 antagonist G15. The release of cytochrome c and activation of caspase-3 in response to GPR30 activation were observed. Data generated from the analysis of animal models and human clinical samples indicate that treatment with the GPR30 agonist relieves testosterone propionate (TP)-induced prostatic epithelial hyperplasia, and that the abundance of GPR30 is negatively associated with prostate volume. On the basis of these results, we propose a novel regulatory mechanism whereby estrogen induces the apoptosis of PECs via GPR30 activation. Inhibition of this activation is predicted to lead to abnormal PEC accumulation, and to thereby contribute to BPH pathogenesis.

[Correlation of oxidative stress with sperm DNA integrity and semen parameters in infertile men with varicocele].

OBJECTIVE: To investigate the relationship of oxidative stress with DNA integrity and semen parameters in infertile men with varicocele (VC). METHODS: This prospective study included 98 infertile males with VC. According to the levels of reactive oxygen species (ROS) in the semen, we divided the patients into a high ROS group (n=44) and a low ROS group (n=54), determined the sperm DNA fragmentation index (DFI), motility and morphology, and analyzed their correlation with ROS in the two groups of patients. RESULTS: Compared with the patients of the low ROS group, those of the high ROS group showed a significantly higher DFI (27.38±8.10 vs 34.49±6.05, P=0.039) and a higher concentration of seminal leukocytes (ï¼»0.65±0.15ï¼½×106/ml vs ï¼»0.86±0.41ï¼½×106/ml, P=0.022), but lower sperm motility (ï¼»36.16±22.83ï¼½% vs ï¼»18.22±25.21ï¼½%, P=0.017), percentage of progressively motile sperm (ï¼»23.34±11.53ï¼½% vs ï¼»16.34±9.22ï¼½%, P=0.041), sperm curvilinear velocity (ï¼»27.03±6.21ï¼½ vs ï¼»20.62±4.38ï¼½ µm/s, P=0.013), and sperm linearity (ï¼»29.75±8.24ï¼½% vs ï¼»18.30±7.93ï¼½%, P=0.024). Spearman correlation analysis indicated that the ROS level was correlated positively with the concentration of seminal leukocytes (r=0.41, P<0.01) and DFI (r=0.21, P=0.006), but negatively with sperm curvilinear velocity (r=－0.24, P=0.017), linearity (r=－0.24, P=0.021), motility (r=－0.31, P=0.002), and the percentage of progressively motile sperm (r=－0.41, P=0.012). Additionally, the sperm DFI manifested a significant negative correlation with sperm motility (r=－0.29, P<0.01) and the percentage of progressively motile sperm (r=－0.34, P<0.01). CONCLUSIONS: The level of seminal ROS is positively correlated with the sperm DFI in infertile men with varicocele, and both the ROS level and DNA integrity are associated with semen parameters.

Autophagy defects suggested by low levels of autophagy activator MAP1S and high levels of autophagy inhibitor LRPPRC predict poor prognosis of prostate cancer patients.

MAP1S (originally named C19ORF5) is a widely distributed homolog of neuronal-specific MAP1A and MAP1B, and bridges autophagic components with microtubules and mitochondria to affect autophagosomal biogenesis and degradation. Mitochondrion-associated protein LRPPRC functions as an inhibitor for autophagy initiation to protect mitochondria from autophagy degradation. MAP1S and LRPPRC interact with each other and may collaboratively regulate autophagy although the underlying mechanism is yet unknown. Previously, we have reported that LRPPRC levels serve as a prognosis marker of patients with prostate adenocarcinomas (PCA), and that patients with high LRPPRC levels survive a shorter period after surgery than those with low levels of LRPPRC. MAP1S levels are elevated in diethylnitrosamine-induced hepatocelular carcinomas in wildtype mice and the exposed MAP1S-deficient mice develop more malignant hepatocellular carcinomas. We performed immunochemical analysis to evaluate the co-relationship among the levels of MAP1S, LRPPRC, P62, and γ-H2AX. Samples were collected from wildtype and prostate-specific PTEN-deficient mice, 111 patients with PCA who had been followed up for 10 years and 38 patients with benign prostate hyperplasia enrolled in hospitals in Guangzhou, China. The levels of MAP1S were generally elevated so the MAP1S-mediated autophagy was activated in PCA developed in either PTEN-deficient mice or patients than their respective benign tumors. The MAP1S levels among patients with PCA vary dramatically, and patients with low MAP1S levels survive a shorter period than those with high MAP1S levels. Levels of MAP1S in collaboration with levels of LRPPRC can serve as markers for prognosis of prostate cancer patients.

MicroRNA-224 and its target CAMKK2 synergistically influence tumor progression and patient prognosis in prostate cancer.

We previously demonstrated that microRNA (miR)-224 expression was significantly reduced in human prostate cancer (PCa) tissues and predicted unfavorable prognosis in patients. However, the underlying mechanisms of miR-224 have not been fully elucidated. In this study, calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) was identified as a target gene of miR-224. Then, we found that enforced expression of miR-224 could suppress PCa cell proliferation and cell cycle by regulating the expression of CAMKK2 in vitro. In addition, the expression levels of miR-224 in PCa tissues were negatively correlated with those of CAMKK2 mRNA significantly (Spearman's correlation: r = -0.66, P = 0.004). Moreover, combined low miR-224 expression and high CAMKK2 expression (miR-224-low/CAMKK2-high) was closely correlated with advanced clinical stage (P = 0.028). Furthermore, PCa patients with miR-224-low/CAMKK2-high expression more frequently had shorter overall survival than those in groups with other expression patterns of two molecules. In conclusion, our data offer the convincing evidence that miR-224 and its target gene CAMKK2 may synergistically contribute to the malignant progression of PCa. Combined detection of miR-224 and CAMKK2 expressions represents an efficient predictor of patient prognosis and may be a novel marker which can provide additional prognostic information in PCa.

[Association of BCL9 expression with prostate cancer clinicopathological features and survival].

OBJECTIVE: B-cell lymphoma 9 (BCL9) as a co-activator for ß-catenin-mediated transcription is highly expressed in tumors. The aim of our study is to investigate the expression of BCL9, and its clinicopathological significance in prostate cancer (PCa). METHODS: Immunohistochemistry was conducted to analyze the expression of BCL9 in 98 PCa samples and 20 benign prostate hyperplasia (BPH) samples. The associations of BCL9 expression with clinicopathological features and prognosis in PCa patients were analyzed with various statistical methods, such as chi-square test, Kaplan-Meier method and log-rank test. RESULTS: The positive rate of BCL9 was 53.1% (52/98) in prostate cancer group, and 25.0% (5/20) in benign group (P=0.022). In addition, BCL9 expression in PCa tissues was significantly associated with Gleason score (P=0.016), and biochemical recurrence (P=0.020). Moreover, Kaplan-Meier survival analysis showed that the higher expression of BCL9 was correlated with shorter biochemical recurrence-free survival (P=0.037). However, BCL9 was not an independent prognostic predictor for biochemical recurrence-free survival in patients with PCa after the multivariate analysis was conducted (Hazard ratio =1.73, P=0.384). CONCLUSION: Our study demonstrates the up-regulation of BCL9 is associated with PCa's early diagnosis and malignant degree.

MicroRNA-224 inhibits progression of human prostate cancer by downregulating TRIB1.

Our previous microarray data showed that microRNA-224 (miR-224) was downregulated in human prostate cancer (PCa) tissues compared with adjacent benign tissues. However, the underlying mechanisms by which miR-224 is involved in PCa remain unclear. In this study, we identified TRIB1 as a target gene of miR-224. Forced expression of miR-224 suppressed PCa cell proliferation, invasion and migration, and promoted cell apoptosis by downregulating TRIB1. Moreover, the expression level of miR-224 in PCa tissues was negatively correlated with that of TRIB1. miR-224 downregulation was frequently found in PCa tissues with metastasis, higher PSA level and clinical stage, whereas TRIB1 upregulation was significantly associated with metastasis. Both miR-224 downregulation and TRIB1 upregulation were significantly associated with poor biochemical recurrence-free survival of patients with PCa. In conclusion, these findings reveal that the aberrant expression of miR-224 and TRIB1 may promote PCa progression and have potentials to serve as novel biomarkers for PCa prognosis.

Elevated levels of mitochondrion-associated autophagy inhibitor LRPPRC are associated with poor prognosis in patients with prostate cancer.

BACKGROUND: Autophagy has recently been found to play important roles in tumorigenesis and leucine-rich pentatricopeptide repeat motif-containing protein (LRPPRC) has been identified as an inhibitor that suppresses autophagy and mitophagy and maintains mitochondrial activity. The authors hypothesized that LRPPRC levels can be used as a biomarker for the diagnosis and prognosis of prostate cancer. METHODS: Immunochemistry analysis was performed to evaluate the levels of LRPPRC in 112 samples collected from patients with prostate adenocarcinoma (PCa) and 38 samples from patients with benign prostatic hyperplasia (BPH) who were enrolled in hospitals in Guangzhou City, China and were followed for 10 years. RESULTS: Significantly higher levels of LRPPRC were found in PCa samples compared with BPH samples. Greater than 75% of patients with PCa demonstrated high levels of LRPPRC whereas only 10% of patients with BPH were found to have similar levels of LRPPRC. The levels of LRPPRC were found to be positively correlated with tumor grade, metastasis, and serum prostate-specific antigen level, but were negatively correlated with hormone therapy sensitivity after 2 years of surgery and overall survival. The association between high levels of LRPPRC and late-stage PCa or hormone therapy insensitivity was confirmed in tissue samples collected from prostate-specific phosphatase and tensin homolog (PTEN)(-/-) mice or hormone-dependent and hormone-independent PCa cell lines. CONCLUSIONS: LRPPRC levels may be used as an independent biomarker for patients with PCa at a late stage with poor prognosis.