PSAT1 enhances the efficacy of the prognosis estimation nomogram model in stage-based clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is associated with a high prevalence of cancer-related deaths. The survival rates of patients are significantly lower in late-stage ccRCC than in early-stage ccRCC, due to the spread and metastasis of late-stage ccRCC, surgery has not reached the goal of radical cure, and the effect of traditional radiotherapy and chemotherapy is poor. Thus, it is crucial to accurately assess the prognosis and provide personalized treatment at an early stage in ccRCC. This study aims to develop an efficient nomogram model for stratifying and predicting the survival of ccRCC patients based on tumor stage. METHODS: We first analyzed the microarray expression data of ccRCC patients from the Gene Expression Omnibus (GEO) database and categorized them into two groups based on the disease stage (early and late stage). Subsequently, the GEO2R tool was applied to screen out the genes that were highly expressed in all GEO datasets. Finally, the clinicopathological data of the two patient groups were obtained from The Cancer Genome Atlas (TCGA) database, and the differences were compared between groups. Survival analysis was performed to evaluate the prognostic value of candidate genes (PSAT1, PRAME, and KDELR3) in ccRCC patients. Based on the screened gene PSAT1 and clinical parameters that were significantly associated with patient prognosis, we established a new nomogram model, which was further optimized to a single clinical variable-based model. The expression level of PSAT1 in ccRCC tissues was further verified by qRT-PCR, Western blotting, and immunohistochemical analysis. RESULTS: The datasets GSE73731, GSE89563, and GSE150404 identified a total of 22, 89, and 120 over-expressed differentially expressed genes (DEGs), respectively. Among these profiles, there were three genes that appeared in all three datasets based on different stage groups. The overall survival (OS) of late-stage patients was significantly shorter than that of early-stage patients. Among the three candidate genes (PSAT1, PRAME, and KDELR3), PSAT1 was shown to be associated with the OS of patients with late-stage ccRCC. Multivariate Cox regression analysis showed that age, tumor grade, neoadjuvant therapy, and PSAT1 level were significantly associated with patient prognosis. The concordance indices were 0.758 and 0.725 for the 3-year and 5-year OS, respectively. The new model demonstrated superior discrimination and calibration compared with the single clinical variable model. The enhancer PSAT1 used in the new model was shown to be significantly overexpressed in tissues from patients with late-stage ccRCC, as demonstrated by the mRNA level, protein level, and pathological evaluation. CONCLUSION: The new prognostic prediction nomogram model of PSAT1 and clinicopathological variables combined was thus established, which may provide a new direction for individualized treatment for different-stage ccRCC patients.

A first-in-class TIMM44 blocker inhibits bladder cancer cell growth.

Mitochondria play a multifaceted role in supporting bladder cancer progression. Translocase of inner mitochondrial membrane 44 (TIMM44) is essential for maintaining function and integrity of mitochondria. We here tested the potential effect of MB-10 (MitoBloCK-10), a first-in-class TIMM44 blocker, against bladder cancer cells. TIMM44 mRNA and protein expression is significantly elevated in both human bladder cancer tissues and cells. In both patient-derived primary bladder cancer cells and immortalized (T24) cell line, MB-10 exerted potent anti-cancer activity and inhibited cell viability, proliferation and motility. The TIMM44 blocker induced apoptosis and cell cycle arrest in bladder cancer cells, but failed to provoke cytotoxicity in primary bladder epithelial cells. MB-10 disrupted mitochondrial functions in bladder cancer cells, causing mitochondrial depolarization, oxidative stress and ATP reduction. Whereas exogenously-added ATP and the antioxidant N-Acetyl Cysteine mitigated MB-10-induced cytotoxicity of bladder cancer cells. Genetic depletion of TIMM44 through CRISPR-Cas9 method also induced robust anti-bladder cancer cell activity and MB-10 had no effect in TIMM44-depleted cancer cells. Contrarily, ectopic overexpression of TIMM44 using a lentiviral construct augmented proliferation and motility of primary bladder cancer cells. TIMM44 is important for Akt-mammalian target of rapamycin (mTOR) activation. In primary bladder cancer cells, Akt-S6K1 phosphorylation was decreased by MB-10 treatment or TIMM44 depletion, but enhanced after ectopic TIMM44 overexpression. In vivo, intraperitoneal injection of MB-10 impeded bladder cancer xenograft growth in nude mice. Oxidative stress, ATP reduction, Akt-S6K1 inhibition and apoptosis were detected in MB-10-treated xenograft tissues. Moreover, genetic depletion of TIMM44 also arrested bladder cancer xenograft growth in nude mice, leading to oxidative stress, ATP reduction and Akt-S6K1 inhibition in xenograft tissues. Together, targeting overexpressed TIMM44 by MB-10 significantly inhibits bladder cancer cell growth in vitro and in vivo.

H3K27 acetylation activated-PDLIM7 promotes castration-resistant prostate cancer progression by inducing O-Glycosylation of YAP1 protein.

Castration-resistant prostate cancer (CRPC) is a fatal disease that evolves from prostate cancer due to drug resistance after long-term androgen deprivation therapy. In this study, we aimed to find novel molecular targets for treating CRPC. Through peptidome, we screened out polypeptides dysregulated in the serum of CRPC patients. According to RT-qPCR analysis and cell viability detection, we chose PDZ and LIM Domain 7 (PDLIM7) as the research object. As demonstrated by loss-of-function assays, silencing of PDLIM7 could suppress CRPC cell proliferation, migration, and angiogenesis. Moreover, PDLIM7 knockdown enhanced the sensitivity of CRPC cells to docetaxel treatment. Subsequently, we found that CBP/p300 increases the H3K27ac level in the PDLIM7 promoter to activate PDLIM7. Mechanism experiments such as IP and western blot revealed that PDLIM7 interacted with YAP1 to induce O-Glycosylation of YAP1 and thus stabilize YAP1 protein. Rescue assays demonstrated that PDLIM7 promoted the malignant processes of CRPC cells through YAP1. Finally, an animal study validated that PDLIM7 aggravated tumor growth. In conclusion, our findings highlighted the oncogenic role of PDLIM7 upregulated by CBP/p300-induced H3K27ac enhancement in CRPC by stabilizing YAP1.

Identification of PRDX5 as A Target for The Treatment of Castration-Resistant Prostate Cancer.

Treatment of castration-resistant prostate cancer (CRPC) is a long-standing clinical challenge. Traditionally, CRPC drugs work by either reducing dihydrotestosterone biosynthesis or blocking androgen receptor (AR) signaling. Here it is demonstrated that AR inhibitor treatment gives rise to a drug-tolerant persister (DTP) state. The thioredoxin/peroxiredoxin pathway is up-regulated in DTP cells. Peroxiredoxin 5 (PRDX5) promotes AR inhibitor resistance and CRPC development. Inhibition of PRDX5 suppresses DTP cell proliferation in culture, dampens CRPC development in animal models, and stabilizes PSA progression and metastatic lesions in patients. Therefore, the study provides a novel mechanism and potential target for the management of castration-resistant prostate cancer.

The Role of Vasodilator-stimulated Phosphoproteins in the Development of Malignant Tumors.

Vasodilator-stimulated phosphoprotein (VASP) is an actin-binding protein that includes three structural domains: Enabled/VASP homolog1 (EVH1), EVH2, and proline-rich (PRR). VASP plays an important role in various cellular behaviors related to cytoskeletal regulation. More importantly, VASP plays a key role in the progression of several malignant tumors and is associated with malignant cell proliferation, invasion, and metastasis. Here, we have summarized current studies on the impact of VASP on the development of several malignant tumors and their mechanisms. This study provides a new theoretical basis for clinical molecular diagnosis and molecular targeted therapy.

A novel PSMA targeted dual-function near-infrared fluorescence and PET probe for the image-guided surgery and detection of prostate cancer.

PURPOSE: Prostate-specific membrane antigen (PSMA) is a promising diagnostic biomarker for prostate cancer (PCa). NYM016, a novel small-molecule PSMA-targeted fluorescence probe for the surgical navigation of PCa, was designed in this work. Furthermore, the potential of the PET agent [68Ga]Ga-NYM016 for the radionuclide imaging of PCa was evaluated. METHODS: NYM016 was designed with the near-infrared fluorescent group Cyanine 7 (Cy7) and the chelating group NOTA. The radioactive probe [68Ga]Ga-NYM016 was designed and synthesized on the basis of NYM016. The abovementioned probes were assessed in PSMA-positive xenograft-bearing models and patients diagnosed with PCa. RESULTS: NYM016 obviously aggregated in the tumor site of the mouse model, and its fluorescence intensity was stable within 24 h. NYM016 was well-tolerated, and no adverse events were found in the clinical study. Moreover, it was also observed in the excised lesions from the patient with PCa, and its fluorescence aggregated at the same site where PSMA was highly expressed. In addition, the PSMA xenograft demonstrated intense [68Ga]Ga-NYM016 uptake at 2.5 min after injection. At 3 h after injection, [68Ga]Ga-NYM016 uptake by the PSMA xenograft gradually increased to 6.40 ± 0.19%ID/g, which was higher that by the blocked and negative groups (2.28 ± 0.07%ID/g, P < 0.05; 2.28 ± 0.22%ID/g, P < 0.05). In the clinical study, [68Ga]Ga-NYM016 was well-tolerated and no adverse events were observed. Substantial accumulation was observed in primary and metastatic lesions in a patient with recurrence with the maximum standardized uptake value of 18.93. Meanwhile, negative [68Ga]Ga-NYM016 uptake was observed at the prostate site of a patient with prostatitis. CONCLUSION: The novel fluorescence probe NYM016 and the radioactive tracer [68Ga]Ga-NYM016 are promising candidates for the surgical navigation and radionuclide imaging of PCa, respectively. TRIAL REGISTRATION: The clinical evaluation of this study was registered at Clinicaltrial.gov (NCT05623878) on 21 Dec, 2022.

2-methoxyestradiol restrains non-small cell lung cancer tumorigenesis through regulating circ_0010235/miR-34a-5p/NFAT5 axis.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the most prevalent and severe malignant tumors in the world and its molecular mechanism is still unclear. In recent years, increasing evidence indicates the significant roles of circRNAs in NSCLC. It has been determined that 2-methoxyestradiol (2-MeOE2) exerts antitumor roles in many cancers. However, the molecular mechanism of 2-MeOE2 in regulating the development of lung cancer needs further elucidation. METHODS: The expression levels of circ_0010235, microRNA-34a-5p (miR-34a-5p), and nuclear factor of activated T cells 5 (NFAT5) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation, apoptosis and invasion were detected by cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) assay, flow cytometry and transwell assays, respectively. The interaction between miR-34a-5p and circ_0010235 or NFAT5 was predicted by bioinformatic software and confirmed by dual-luciferase reporter assay. RESULTS: Our data showed 2-MeOE2 hindered cell proliferation, invasion and induced apoptosis in NSCLC, which could be reversed by upregulation of circ_0010235 and NFAT5 or miR-34a-5p knockdown. Circ_0010235 and NFAT5 expression levels were increased, and miR-34a-5p expression level was decreased in NSCLC tissues and cells. In addition, 2-MeOE2 treatment suppressed the expression of circ_0010235 and NFAT5 while promoted the expression of miR-34a-5p. Furthermore, circ_0010235 functioned as a molecular sponge of miR-34a-5p to regulate NFAT5 expression. Knockdown of circ_0010235 or 2-MeOE2 treatment constrained tumor growth in vivo, and circ_0010235 depletion enhanced the inhibitory effect of 2-MeOE2 on tumor growth in vivo. CONCLUSION: These findings demonstrated that 2-MeOE2 retarded NSCLC progression by modulating the circ_0010235/miR-34a-5p/NFAT5 axis, thus providing a new perspective for 2-MeOE2 treatment in NSCLC.

TROAP Promotes the Proliferation, Migration, and Metastasis of Kidney Renal Clear Cell Carcinoma with the Help of STAT3.

Kidney renal clear cell carcinoma (KIRC) is a subtype of renal cell carcinoma that threatens human health. The mechanism by which the trophinin-associated protein (TROAP)-an important oncogenic factor-functions in KIRC has not been studied. This study investigated the specific mechanism by which TROAP functions in KIRC. TROAP expression in KIRC was analyzed using the RNAseq dataset from the Cancer Genome Atlas (TCGA) online database. The Mann-Whitney U test was used to analyze the expression of this gene from clinical data. The Kaplan-Meier method was used for the survival analysis of KIRC. The expression level of TROAP mRNA in the cells was detected using qRT-PCR. The proliferation, migration, apoptosis, and cell cycle of KIRC were detected using Celigo, MTT, wound healing, cell invasion assay, and flow cytometry. A mouse subcutaneous xenograft experiment was designed to demonstrate the effect of TROAP expression on KIRC growth in vivo. To further investigate the regulatory mechanism of TROAP, we performed co-immunoprecipitation (CO-IP) and shotgun liquid chromatography-tandem mass spectrometry (LC-MS). TCGA-related bioinformatics analysis showed that TROAP was significantly overexpressed in KIRC tissues and was related to higher T and pathological stages, and a poor prognosis. The inhibition of TROAP expression significantly reduced the proliferation of KIRC, affected the cell cycle, promoted cell apoptosis, and reduced cell migration and invasion. The subcutaneous xenograft experiments showed that the size and weight of the tumors in mice were significantly reduced after TROAP-knockdown. CO-IP and post-mass spectrometry bioinformatics analyses revealed that TROAP may combine with signal transducer and activator of transcription 3 (STAT3) to achieve tumor progression in KIRC; this was verified by functional recovery experiments. TROAP may regulate KIRC proliferation, migration, and metastasis by binding to STAT3.

A first-in-class HBO1 inhibitor WM-3835 inhibits castration-resistant prostate cancer cell growth in vitro and in vivo.

The prognosis and overall survival of castration-resistant prostate cancer (CRPC) patients are poor. The search for novel and efficient anti-CRPC agents is therefore extremely important. WM-3835 is a cell-permeable, potent and first-in-class HBO1 (KAT7 or MYST2) inhibitor. Here in primary human prostate cancer cells-derived from CRPC patients, WM-3835 potently inhibited cell viability, proliferation, cell cycle progression and in vitro cell migration. The HBO1 inhibitor provoked apoptosis in the prostate cancer cells. It failed to induce significant cytotoxicity and apoptosis in primary human prostate epithelial cells. shRNA-induced silencing of HBO1 resulted in robust anti-prostate cancer cell activity as well, and adding WM-3835 failed to induce further cytotoxicity in the primary prostate cancer cells. Conversely, ectopic overexpression of HBO1 further augmented primary prostate cancer cell proliferation and migration. WM-3835 inhibited H3-H4 acetylation and downregulated several pro-cancerous genes (CCR2, MYLK, VEGFR2, and OCIAD2) in primary CRPC cells. Importantly, HBO1 mRNA and protein levels are significantly elevated in CRPC tissues and cells. In vivo, daily intraperitoneal injection of WM-3835 potently inhibited pPC-1 xenograft growth in nude mice, and no apparent toxicities detected. Moreover, intratumoral injection of HBO1 shRNA adeno-associated virus (AAV) suppressed the growth of primary prostate cancer xenografts in nude mice. H3-H4 histone acetylation and HBO1-dependent genes (CCR2, MYLK, VEGFR2, and OCIAD2) were remarkably decreased in WM-3835-treated or HBO1-silenced xenograft tissues. Together, targeting HBO1 by WM-3835 robustly inhibits CRPC cell growth.

The diagnostic role and mechanistic functions of exosomal lncRNAs in prostate cancer.

Exosomes are small membrane-enclosed vesicles that are released by most living cells and harbor a diverse array of proteins, nucleic acids, and lipid cargos. These exosomes offer valuable biomarkers that may offer insights regarding as a range of physiological and pathological processes, including immune responses, cancer development, pregnancy, and diseases of the central nervous system. With the development of high-throughput technologies, the vital functions of long non-coding RNAs (lncRNAs) have been gradually entered people's vision and become new research hotspots. Nowadays, lncRNAs can play important roles in cancer progression by combining with miRNAs, activating molecular targets and other ways, and are also related to the diagnosis, treatment and prognosis for cancer, such as prostate cancer. Current review focused on the summary of diagnostic roles and mechanistic functions about exosomal lncRNAs in prostate cancer.

NUPR1 imparts oncogenic potential in bladder cancer.

BACKGROUND: NUPR1, or p8, is a small chromatin protein that plays a central role in the resistance to treatment and progression of cancer. Nevertheless, the molecular mechanism of NUPR1 in bladder cancer (BLCA) remains unclear. METHODS: We used online databases and immunohistochemistry (IHC) to explore the expression of NUPR1 in BLCA tissues and controls. Lentivirus-mediated small interfering ribonucleic acid (siRNA) was used to knockdown the expression of NUPR1 in two human BLCA cell lines. We used an in vivo experiment to investigate the effect of NUPR1 knockdown on the growth of BLCA. Moreover, an in silico analysis was conducted to assess the differential expression profile after NUPR1 interference. The CIBERSORT algorithm was utilized to evaluate the effects of tumor-infiltrating immune cells among BLCA patients. RESULTS: The expression of NUPR1 in BLCA tissues was significantly higher than in the control. NUPR1 expression was also positively correlated with the stage of BLCA. After lentivirus-mediated interference, the expression of NUPR1 was significantly down-regulated in BLCA cell lines. The cell cycle was blocked in G1 phase and the cell proportion of S phase was decreased in both two cell lines. Moreover, in vivo experiment revealed that the tumor growth of BLCA can be delayed by inhibiting the expression of NUPR1. Both in silico analysis and functional experiments revealed that NUPR1 was correlated with epithelial-mesenchymal transition (EMT). We also revealed that macrophages were the most related immune cells associated with the expression of NUPR1 in BLCA. CONCLUSIONS: This study suggests that NUPR1 plays a carcinogenic role in BLCA. NUPR1 lentivirus-mediated interference could interfere with cycle progression of the BLCA cell, resulting in cell cycle arrest in the G1-phase. The carcinogenic effect of NUPR1 in BLCA is likely achieved through EMT. NUPR1 is correlated with the M0-type macrophage markers CD68 and CD11b-integrin.

Research on the effects of rs1800566 C/T polymorphism of NAD(P)H quinone oxidoreductase 1 gene on cancer risk involves analysis of 43,736 cancer cases and 56,173 controls.

Objective: A two-electron reductase known as NQO1 [NAD(P)H quinone oxidoreductase 1] is regarded as an excellent anticancer target. Studies have found that rs1800566 polymorphism of NQO1 is linked to different cancers, but their associations remain controversial. Methods: In the present work, we selected to do a comprehensive meta-analysis to analyze their correlation. We performed searches on PubMed, Embase, Google Scholar, Chinese database, and Web of Science. The results we obtained covered all publications before April 3, 2022. Results: There were 176 case-control studies among them, with 56,173 corresponding controls and 43,736 cancer cases. We determined that the NQO1 rs1800566 polymorphism was not related to the cancer risk by calculating 95% confidence intervals and odds ratios. However, stratified genotyping showed that this polymorphism was protective against hepatocellular carcinoma, renal cell carcinoma, and gastric cancer. In addition, on dividing cancer into six systems, the association with gastrointestinal cancer decreased. In the race-based subgroup, a decreasing trend was observed in Asians, while an increasing trend was found among Caucasians, Africans, and mixed populations. The decreased correlation in the hospital-based subgroup was also detected. Conclusion: Current study shows that rs1800566 polymorphism of NQO1 was linked to cancer susceptibility and maybe as a tumor marker in their development.

Naturally Equipped Urinary Exosomes Coated Poly (2-ethyl-2-oxazoline)-Poly (D, L-lactide) Nanocarriers for the Pre-Clinical Translation of Breast Cancer.

Recently, biomimetic nanoparticles for tumor-targeted therapy have attracted intensifying interest. Although exosomes are an excellent biomimetic material, numerous challenges are still hindering its clinical applications, such as low yield, insufficient targeting efficiency, and high cost. In this work, urinary exosomes (UEs) with high expression of CD9 and CD47 were extracted from breast cancer patients by a non-invasive method. Here, a nanotechnology approach is reported for tumor homologous targeting via CD9 and phagocytosis escape via CD47 through UE-coated poly (2-ethyl-2-oxazoline)-poly (D, L-lactide) (PEOz-PLA) nanoparticles (UEPP NPs). The cytotoxic agent doxorubicin (DOX)-loaded UEPP (UEPP-D) NPs with an initial particle size of 61.5 nm showed a burst release under acidic condition mimicking the tumor microenvironment. In vitro experiments revealed that UEPP-D NPs exhibited significantly improved cellular uptake, cytotoxicity, and apoptosis in MCF-7 cell lines as compared to DOX-loaded PEOz-PLA nanoparticles (PP-D NPs) and free DOX. More importantly, anti-phagocytosis and pharmacokinetic studies confirmed that UEPP-D NPs had superior immune escape ability and significantly prolonged the drug's bloodstream circulation in vivo. Finally, UEPP-D NPs showed a markedly higher antitumor efficacy and lower side-toxicity in MCF-7 tumor bearing nude mice model. Thus, this versatile nano-system with immune escape, homologous targeting, and rapid response release characteristics could be a promising tool for breast cancer treatment.

Functions and mechanisms of N6­methyladenosine in prostate cancer (Review).

Prostate cancer (PCa) has long been a major public health problem affecting men worldwide. Even with treatment, it can develop into castration­resistant PCa. With the continuous advancement in epigenetics, researchers have explored N6­methyladenosine (m6A) in search of a more effective and lasting treatment for PCa. m6A is widely distributed in mammalian cells and influences various aspects of mRNA metabolism. Recently, it has been associated with the development or suppression of various types of cancer, including PCa. This review summarizes the recent findings on m6A regulation and its functions and mechanisms in cells, focusing on the various functional proteins operating within m6A in PCa cells. Moreover, the potential clinical value of exploiting m6A modification as an early diagnostic marker in PCa diagnosis and therapeutics was discussed. m6A may also be used as an indicator to evaluate treatment outcome and prognosis.

N-glycosylation of GDF15 abolishes its inhibitory effect on EGFR in AR inhibitor-resistant prostate cancer cells.

Castration-resistance of prostate cancer is one of the most challenging clinical problems. In the present study, we have performed proteomics and glycomics using LNCaP model. Growth differentiation factor-15 (GDF15) level is increased in androgen receptor (AR) inhibitor-resistant cells and the inhibitory effect of GDF15 on epithelial growth factor receptor (EGFR) pathway is relieved by GDF15 N70 glycosylation. Interference of GDF15 (siRNA or N70Q dominant negative) or EGFR pathway (inhibitor or siRNA for EGFR, SRC or ERK) decreases the resistant-cell survival in culture and tumor growth in mice. Our study reveals a novel regulatory mechanism of prostate cancer AR inhibitor resistance, raises the possibility of AR/SRC dual-targeting of castration-resistance of prostate cancer, and lays foundation for the future development of selective inhibitors of GDF15 glycosylation.

Lysine demethylase 5A promotes prostate adenocarcinoma progression by suppressing microRNA-330-3p expression and activating the COPB2/PI3K/AKT axis in an ETS1-dependent manner.

Lysine demethylase 5A (KDM5A) is a histone demethylase frequently involved in cancer progression. This research aimed to explore the function of KDM5A in prostate adenocarcinoma (PRAD) and the molecular mechanism. KDM5A was highly expressed in collected PRAD tissues and acquired PRAD cells. High KDM5A expression was correlated with reduced survival and poor prognosis of patients with PRAD. Knockdown of KDM5A suppressed the proliferation, colony formation, migration, and invasiveness of PRAD cells and reduced angiogenesis ability of endothelial cells. Downstream molecules implicated in KDM5A mediation were predicted using integrated bioinformatic analyses. KDM5A enhanced ETS proto-oncogene 1 (ETS1) expression through demethylation of H3K4me2 at its promoter. ETS1 suppressed the transcription activity of miR-330-3p, and either further ETS1 overexpression or miR-330-3p inhibition blocked the functions of KDM5A knockdown in PRAD. miR-330-3p targeted coatomer protein complex subunit ß2 (COPB2) mRNA. Downregulation of miR-330-3p restored the expression of COPB2 and activated the PI3K/AKT pathway in PRAD. The results in vitro were reproduced in vivo where KDM5A downregulation suppressed the growth and metastasis of xenograft tumors in nude mice. In conclusion, this study demonstrated that KDM5A promoted PRAD by suppressing miR-330-3p and activating the COPB2/PI3K/AKT axis in an ETS1-dependent manner.

Upregulation of COPB2 Promotes Prostate Cancer Proliferation and Invasion Through the MAPK/TGF-ß Signaling Pathway.

There is increasing evidence that coatomer protein complex subunit beta 2 (COPB2) plays an important role in various cancer types. This study explored the role and the downstream mediators of COPB2 in prostate cancer (PCa). The expression of COPB2 was determined by the Cancer Genome Atlas database and enzyme-linked immunosorbent assay. COPB2 expression was upregulated in PCa tissues and correlated with Gleason score, biochemical recurrence, and poor prognosis. The functional roles of COPB2 in PCa were verified through a series of experiments. Knocking down COPB2 expression inhibited the growth and clonogenesis of PCa cells, promoted cell apoptosis, and inhibited the ability of scratch repair, invasion of PCa cells, and tumor growth in Nude mice. To analyze downstream signaling pathways, ingenuity pathway analysis, GSEA, and whole-genome expression spectrum GeneChip analysis were used. Western blot revealed that COPB2 expression promoted the proliferation and invasion of PCa cells by regulating the MAPK/TGF-ß signaling pathway. The interacting protein (nuclear protein 1, NUPR1) was identified via Co-IP, real-time PCR, Western blot, and TCGA database in sampled tissues. The expressions of the interaction proteins NUPR1 and COPB2 were negatively regulated by each other. COPB2 could be a new biomarker for PCa diagnosis and monitoring and to provide a theoretical basis for identifying effective drug intervention targets through in-depth mechanistic studies.

Comprehensive Analysis of 29,464 Cancer Cases and 35,858 Controls to Investigate the Effect of the Cytotoxic T-Lymphocyte Antigen 4 Gene rs231775 A/G Polymorphism on Cancer Risk.

In our previous studies, we found that the rs231775 polymorphism of cytotoxic T-lymphocyte antigen 4 (CTLA-4) is associated with risks of different cancer types; however, the association remains controversial and ambiguous, so we conducted an in-depth meta-analysis to verify the association. A complete search of the PubMed, Google Scholar, Embase, Chinese databases, and Web of Science was conducted without regard to language limitations, covering all publications since November 20, 2021. The search criteria for cancer susceptibility associated with the polymorphism in the CTLA-4 gene rs231775 resulted in 87 case-control studies with 29,464 cases and 35,858 controls. The association strength was analyzed using odds ratios and 95% confidence intervals. Overall, we found that the CTLA-4 rs231775 polymorphism may reduce cancer risk. A stratified cancer type analysis showed that CTLA-4 rs231775 polymorphism was a risk factor for colorectal cancer and thyroid cancer; on the other hand, it was a protective factor for breast cancer, liver cancer, cervical cancer, bone cancer, head and neck, and pancreatic cancer. We also classified cancer into five systems and observed an increased association with digestive tract cancer, decreased associations with orthopedic tumors, tumors of the urinary system, and gynecological tumors. In the subgroup based on race, decreased relationships were observed in both Asians and Caucasians. The same decreased association was also shown in the analysis of the source of control analysis. Our present study indicates that the CTLA-4 rs231775 polymorphism contributes to cancer development and aggression.

Associations of Genetic Polymorphisms of mTOR rs2295080 T/G and rs1883965 G/A with Susceptibility of Urinary System Cancers.

BACKGROUND: Genetic polymorphisms in mammalian target of rapamycin (mTOR) signaling axis can influence the susceptibility of cancer. The relationship between mTOR gene variants rs2295080 T/G and rs1883965 G/A and the risk of cancer remains inconsistent. The present study is aimed at comprehensively investigating the association between mTOR polymorphisms and susceptibility to cancer. METHODS: We conducted a comprehensive assessment using odds ratios (ORs), corresponding 95% confidence intervals (CIs), and in silico tools to evaluate the effect of mTOR variations. Immunohistochemical staining (IHS) and GSEA analysis were used to investigate the expression of mTOR in urinary system cancer. RESULTS: The pooled analysis involved 22 case-control studies including 14,747 cancer patients and 16,399 controls. The rs2295080 T/G polymorphism was associated with the risk of cancer (G-allele versus T-allele, OR = 0.89, 95%CI = 0.80-0.98, P = 0.023; GT versus TT, OR = 0.88, 95%CI = 0.81-0.96, P = 0.004; GG+GT versus TT, OR = 0.87, 95%CI = 0.78-0.96, P = 0.008), especially for cancers of the urinary system, breast, and blood. Variation rs1883965 G/A was associated with cancer susceptibility, especially for digestive cancer. IHS analysis showed that mTOR was upregulated in prostate and bladder cancer. GSEA revealed that the insulin signaling pathway, lysine degradation pathway, and mTOR signaling pathway were enriched in the high mTOR expression group. CONCLUSIONS: The mTOR rs2295080 T/G polymorphism may be associated with susceptibility of urinary cancer. The expression of mTOR is positively correlated with tumor malignancy in prostate cancer.

Long Non-coding RNAs LINC01679 as a Competitive Endogenous RNAs Inhibits the Development and Progression of Prostate Cancer via Regulating the miR-3150a-3p/SLC17A9 Axis.

Long non-coding RNAs (lncRNAs) have been indicated as the candidate factors to predict cancer prognosis. However, it is still unknown whether lncRNA combinations may be utilized for predicting overall survival (OS) of prostate cancer (PCa). The present work focused on selecting the potent OS-related lncRNA signature for PCa and studying its molecular mechanism to enhance the prognosis prediction accuracy. Differentially expressed lncRNAs (DElncRNAs) or differentially expressed genes (DEGs) were obtained based on TCGA database by R software "edgeR" package. lncRNAs or mRNAs significantly related to PCa were screened through univariate as well as multivariate Cox regression, for the construction of the risk model for prognosis prediction. Moreover, this constructed risk model was validated through ROC analysis, univariate regression, and Kaplan-Meier (KM) analysis. Additionally, we built a lncRNA-miRNA-mRNA ceRNA network through bioinformatics analysis. Colony formation, CCK-8, flow cytometry, scratch, and Transwell assays were performed based on PCa cells subjected to small interfering RNA (siRNA) targeting LINC01679/SLC17A9 and vector expressing LINC01679/SLC17A9 transfection. Thereafter, the ceRNA mechanism was clarified via qRT-PCR, Western blotting (WB), RNA pull-down, and luciferase reporter assays. Nude mouse tumor xenograft was established to examine LINC01679's oncogenicity within PCa cells. According to our results, LINC01679 depletion promoted cell proliferation, metastasis, tumor growth, and inhibited cell apoptosis in vivo and in vitro, which was also associated with poor survival. LINC01679 regulated miR-3150a-3p level by sponging it. Importantly, miR-3150a-3p overexpression was related to the increased proliferation and decreased apoptosis of PCa cells. Rescue assays suggested that miR-3150a-3p mimics rescued the repression on PCa progression mediated by LINC01679 upregulation, but SLC17A9 downregulation reversed the miR-3150a-3p inhibitor-mediated repression on PC progression. Importantly, SLC17A9 downregulation rescued the repression on PCa progression mediated by LINC01679 upregulation. LINC01679 and SLC17A9 are tightly associated with certain clinicopathological characteristics of PCa and its prognostic outcome. In addition, LINC01679 is the ceRNA that suppresses PCa development through modulating the miR-3150a-3p/SLC17A9 axis.