IFIT3 (Interferon Induced Protein with Tetratricopeptide Repeats 3) Modulates STAT1 Expression in small Extracellular Vesicles

We have previously shown that the αvβ6 integrin plays a key role in promoting prostate cancer (PrCa) as it can be transferred to recipient cells via small extracellular vesicles (sEVs). Furthermore, we have reported in a proteomic analysis that αvβ6 integrin downregulation increases the expression of IFIT3 (interferon induced protein with tetratricopeptide repeats 3) in PrCa cells and their derived sEVs. IFIT3 is a protein well known for being an antiviral effector, but recently its role in cancer has also been elucidated. To study the relationship between IFIT3 and STAT1 (signal transducer and activator of transcription 1), an upstream regulator of IFIT3, in PrCa cells and their released sEVs, we used CRISPR/Cas9 techniques to downregulate the expression of the β6 integrin subunit, IFIT3 or STAT1. Our results show that IFIT3 and STAT1 are highly expressed in PrCa cells devoid of the β6 integrin subunit. However, IFIT3 but not STAT1, is present in sEVs derived from PrCa cells lacking the β6 integrin subunit. We demonstrate that loss of IFIT3 generates sEVs enriched in STAT1 but reduces the levels of STAT1 in the cells. As expected, IFIT3 is not detectable in STAT1 negative cells or sEVs. We thus propose that the observed STAT1 enrichment in sEVs is a compensatory mechanism for the loss of IFIT3. Overall, these results provide new insights into the intrinsic role of IFIT3 as a regulator of STAT1 expression in PrCa derived sEVs and in intercellular communication in PrCa.

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Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2)

Cancers ◽

10.3390/cancers13163959 ◽

2021 ◽

Vol 13 (16) ◽

pp. 3959

Author(s):

Oluwaseun Adebayo Bamodu ◽

Yuan-Hung Wang ◽

Chen-Hsun Ho ◽

Su-Wei Hu ◽

Chia-Da Lin ◽

...

Keyword(s):

Prostate Cancer ◽

Disease Progression ◽

Therapy Resistance ◽

Calcium Signal ◽

Signal Transducer ◽

Castration Resistance ◽

Castration Resistant

Background: prostate cancer (PCa) is a principal cause of cancer-related morbidity and mortality. Castration resistance and metastasis are clinical challenges and continue to impede therapeutic success, despite diagnostic and therapeutic advances. There are reports of the oncogenic activity of genetic suppressor element (GSE)1 in breast and gastric cancers; however, its role in therapy resistance, metastasis, and susceptibility to disease recurrence in PCa patients remains unclear. Objective: this study investigated the role of aberrantly expressed GSE1 in the metastasis, therapy resistance, relapse, and poor prognosis of advanced PCa. Methods: we used a large cohort of multi-omics data and in vitro, ex vivo, and in vivo assays to investigate the potential effect of altered GSE1 expression on advanced/castration-resistant PCa (CRPC) treatment responses, disease progression, and prognosis. Results: using a multi-cohort approach, we showed that GSE1 is upregulated in PCa, while tumor-associated calcium signal transducer 2 (TACSTD2) is downregulated. Moreover, the direct, but inverse, correlation interaction between GSE1 and TACSTD2 drives metastatic disease, castration resistance, and disease progression and modulates the clinical and immune statuses of patients with PCa. Patients with GSE1highTACSTD2low expression are more prone to recurrence and disease-specific death than their GSE1lowTACSTD2high counterparts. Interestingly, we found that the GSE1–TACSTD2 expression profile is associated with the therapy responses and clinical outcomes in patients with PCa, especially those with metastatic/recurrent disease. Furthermore, we demonstrate that the shRNA-mediated targeting of GSE1 (shGSE1) significantly inhibits cell proliferation and attenuates cell migration and tumorsphere formation in metastatic PC3 and DU145 cell lines, with an associated suppression of VIM, SNAI2, and BCL2 and the concomitant upregulation of TACSTD2 and BAX. Moreover, shGSE1 enhances sensitivity to the antiandrogens abiraterone and enzalutamide in vitro and in vivo. Conclusion: these data provide preclinical evidence of the oncogenic role of dysregulated GSE1–TACSTD2 signaling and show that the molecular or pharmacological targeting of GSE1 is a workable therapeutic strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing CRPC to treatment, and repressing the metastatic/recurrent phenotypes of patients with PCa.

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Role of Precision Oncology in Type II Endometrial and Prostate Cancers in the African Population: Global Cancer Genomics Disparities

International Journal of Molecular Sciences ◽

10.3390/ijms23020628 ◽

2022 ◽

Vol 23 (2) ◽

pp. 628

Author(s):

Rahaba Marima ◽

Rodney Hull ◽

Mandisa Mbeje ◽

Thulo Molefi ◽

Kgomotso Mathabe ◽

...

Keyword(s):

Prostate Cancer ◽

Endometrial Cancer ◽

African Ancestry ◽

African Population ◽

Precision Oncology ◽

Type Ii ◽

Incidence And Mortality ◽

Prostate Cancers ◽

The Relationship

Precision oncology can be defined as molecular profiling of tumors to identify targetable alterations. Emerging research reports the high mortality rates associated with type II endometrial cancer in black women and with prostate cancer in men of African ancestry. The lack of adequate genetic reference information from the African genome is one of the major obstacles in exploring the benefits of precision oncology in the African context. Whilst external factors such as the geography, environment, health-care access and socio-economic status may contribute greatly towards the disparities observed in type II endometrial and prostate cancers in black populations compared to Caucasians, the contribution of African ancestry to the contribution of genetics to the etiology of these cancers cannot be ignored. Non-coding RNAs (ncRNAs) continue to emerge as important regulators of gene expression and the key molecular pathways involved in tumorigenesis. Particular attention is focused on activated/repressed genes and associated pathways, while the redundant pathways (pathways that have the same outcome or activate the same downstream effectors) are often ignored. However, comprehensive evidence to understand the relationship between type II endometrial cancer, prostate cancer and African ancestry remains poorly understood. The sub-Saharan African (SSA) region has both the highest incidence and mortality of both type II endometrial and prostate cancers. Understanding how the entire transcriptomic landscape of these two reproductive cancers is regulated by ncRNAs in an African cohort may help elucidate the relationship between race and pathological disparities of these two diseases. This review focuses on global disparities in medicine, PCa and ECa. The role of precision oncology in PCa and ECa in the African population will also be discussed.

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Extracellular Vesicles-Mediated Transfer of miRNA Let-7b from PC3 Cells to Macrophages

Genes ◽

10.3390/genes11121495 ◽

2020 ◽

Vol 11 (12) ◽

pp. 1495

Author(s):

Egidia Costanzi ◽

Rita Romani ◽

Paolo Scarpelli ◽

Ilaria Bellezza

Keyword(s):

Prostate Cancer ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Inflammatory Responses ◽

Target Cells ◽

Prostate Cell ◽

Prostate Cancer Therapy ◽

Reverse Transcription Quantitative Pcr ◽

Pc3 Cells

Prostate-derived extracellular vesicles (pEVs) may represent a way to selectively transport cargo molecules from the producing cells to the target cells to allow biological events, both in physiological and pathological circumstances. pEVs cargo participates in the modulation of the inflammatory responses in physiological conditions and during cancer progression. In the present study, we examined the expression levels of miRNA Let-7b, in both precursor and mature forms, in noncancerous and cancerous prostate cell lines, PNT2 and PC3 respectively, and in their extracellular vesicles (EVs) using reverse-transcription quantitative PCR strategies. We showed that miRNA Let-7b was highly expressed in noncancerous cells and strongly decreased in cancerous PC3 cells, while the opposite was observed in the respective EVs, thus supporting the tumor suppressor role of miRNA Let7-b. We also demonstrated that miRNA Let-7b can be transferred to THP-1 cells via EVs, which are known to induce TAM-like polarization. Our results support the view that miRNA Let-7 b, contained in PC3-derived EVs, is associated with the increase in the miRNA Let7-b observed in TAM-like macrophages. Overall, our results indicate that circulating EV-loaded miRNA might be useful biomarkers for prostate cancer progression and might also support a possible use of pEVs as targets for prostate cancer therapy.

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The role of cancer-associated fibroblasts and their extracellular vesicles in prostate cancer progression

European Urology Open Science ◽

10.1016/s2666-1683(20)33819-2 ◽

2020 ◽

Vol 19 ◽

pp. e1817

Author(s):

J. Linxweiler ◽

A. Zaccagnino ◽

D. Himbert ◽

T. Hajili ◽

P. Zeuschner ◽

...

Keyword(s):

Prostate Cancer ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Cancer Associated Fibroblasts ◽

Prostate Cancer Progression

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Role of splice variants in the metastatic progression of prostate cancer

Biochemical Society Transactions ◽

10.1042/bst20120026 ◽

2012 ◽

Vol 40 (4) ◽

pp. 870-874 ◽

Cited By ~ 16

Author(s):

Rachel M. Hagen ◽

Michael R. Ladomery

Keyword(s):

Prostate Cancer ◽

Cancer Metastasis ◽

Splice Variants ◽

Human Cancer ◽

Metastatic Potential ◽

Metastatic Progression ◽

Cellular Phenotype ◽

Prostate Cancer Metastasis ◽

The Relationship

AS (alternative splicing) and its role in disease, especially cancer, has come to forefront in research over the last few years. Alterations in the ratio of splice variants have been widely observed in cancer. Splice variants of cancer-associated genes have functions that can alter cellular phenotype, ultimately altering metastatic potential. As metastases are the cause of approximately 90% of all human cancer deaths, it is crucial to understand how AS is dysregulated in metastatic disease. We highlight some recent studies into the relationship between altered AS of key genes and the initiation of prostate cancer metastasis.

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Extracellular Vesicles in Prostate Cancer: New Future Clinical Strategies?

BioMed Research International ◽

10.1155/2014/561571 ◽

2014 ◽

Vol 2014 ◽

pp. 1-14 ◽

Cited By ~ 14

Author(s):

Ilaria Giusti ◽

Vincenza Dolo

Keyword(s):

Prostate Cancer ◽

Extracellular Vesicles ◽

Specific Antigen ◽

Specific Marker ◽

Cellular Origin ◽

Organ Specific ◽

Potential Use

Prostate cancer (PCa) is the most common cancer—excluding skin tumors—in men older than 50 years of age. Over time, the ability to diagnose PCa has improved considerably, mainly due to the introduction of prostate-specific antigen (PSA) in the clinical routine. However, it is important to take into account that although PSA is a highly organ-specific marker, it is not cancer-specific. This shortcoming suggests the need to find new and more specific molecular markers. Several emerging PCa biomarkers have been evaluated or are being assessed for their potential use. There is increasing interest in the prospective use of extracellular vesicles as specific markers; it is well known that the content of vesicles is dependent on their cellular origin and is strongly related to the stimulus that triggers the release of the vesicles. Consequently, the identification of a disease-specific molecule (protein, lipid or RNA) associated with vesicles could facilitate their use as novel biological markers. The present review describes severalin vitrostudies that demonstrate the role of vesicles in PCa progression and severalin vivostudies that highlight the potential use of vesicles as PCa biomarkers.

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Periprostatic venous androgen levels in a subset of patients with prostate cancer: An investigation into a novel role of testosterone in localized prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.341 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 341-341

Author(s):

Lewis Thomas ◽

Mohammad Alyamani ◽

Jianbo Li ◽

Andrei Purysko ◽

Eric A. Klein ◽

...

Keyword(s):

Prostate Cancer ◽

Prostate Volume ◽

Venous Blood ◽

Venous Drainage ◽

Increased Risk ◽

Vein Diameter ◽

Clinically Significant ◽

The Relationship ◽

Androgen Levels

341 Background: While androgens drive prostate cancer (PCa), studies of systemic levels in eugonadal patients have not shown a relationship with development or progression of PCa. This study characterizes the relationship between systemic, local venous, and tissue androgen levels to understand the regulation and influence of androgens on localized PCa. Methods: Peripheral & periprostatic venous blood & prostate tissue were collected from patients undergoing radical prostatectomy (RP). Androgen levels (testosterone (T) and dihydrotestosterone (DHT)) were assessed by mass spectrometry. PCa grade and stage, PSA, prostate volume, and periprostatic vein diameter (PPVD) on MRI were recorded. A second cohort of patients undergoing just prostate MRI (non-surgical) was assessed to investigate the relationship between PPVD and disease severity. Results: Samples were collected from 176 patients. Analysis identified a subset of patients with elevated periprostatic T (ppT) relative to systemic T (sT) including 25% with ppT/sT > 2, 14% with ppT/sT > 4, and 7% with ppT/sT > 10. Patients with ppT/sT > 4 had supraphysiologic T levels in the periprostatic venous blood (mean 4223ng/mL). These patients also had higher than predicted levels of tissue T and DHT (tT/sT of 0.48 vs 0.24 (p = 0.004) and tDHT/sT of 7.31 vs 4.72 (p = 0.011)). In the surgical cohort, PPVD was increased in patients with elevated ppT/sT levels (5.8mm vs 3.7mm, p = 0.013). In the biopsy cohort (n = 200), increased PPVD was associated with an increased risk of diagnosis of PCa (4.39mm vs 3.43mm p = 0.006) and clinically significant PCa (4.35mm vs 3.43mm p = 0.01). Conclusions: In a subset of patients with PCa, periprostatic venous T levels were highly elevated compared to peripheral levels. Tissue T and DHT were also increased, and MRI demonstrated increased PPVD. We hypothesize that collateralization of venous drainage from the gonadal vein leads to both high local T and dilated veins. In a biopsy cohort, increased PPVD was associated with an increased risk of diagnosis of any and clinically significant PCa, suggesting that high periprostatic androgen levels may play a role in development of PCa.

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Extracellular Vesicles from Human Advanced-Stage Prostate Cancer Cells Modify the Inflammatory Response of Microenvironment-Residing Cells

Cancers ◽

10.3390/cancers11091276 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1276 ◽

Cited By ~ 2

Author(s):

Letizia Mezzasoma ◽

Egidia Costanzi ◽

Paolo Scarpelli ◽

Vincenzo Nicola Talesa ◽

Ilaria Bellezza

Keyword(s):

Prostate Cancer ◽

Inflammatory Response ◽

Cancer Cells ◽

Extracellular Vesicles ◽

Cell Communication ◽

Advanced Stage ◽

Prostate Cell ◽

Caspase 1 ◽

Pc3 Cells

Prostate cancer (PCa) progression is strictly associated with microenvironmental conditions, which can be modified by cancer-released extracellular vesicles (EVs), important mediators of cell-cell communication. However, the role of EVs in the inflammatory cross-talk between cancer cells and microenvironment-residing cells remains largely unknown. To evaluate the role of EVs in the tumour microenvironment, we treated the non-cancerous prostate cell line PNT2 with EVs isolated from advanced-stage prostate cancer PC3 (PC3-EVs). Caspase-1-mediated IL-1β maturation was evaluated after 24 h incubation with EVs. Moreover, the effect of PC3-EVs on differentiated macrophagic THP-1 cells was assessed by analyzing cytokine expression and PC3 cells migration and proliferation profiles. We illustrated that PC3 cells contain active NLRP3-inflammasome cascade and secrete IL-1β. PC3-EVs affect the PNT2 inflammatory response, inducing caspase-1-mediated IL-1β maturation via ERK1/2-mediated lysosomal destabilization and cathepsin B activation. We also verified that PC3-EVs induce a functional TAM-like polarization in differentiated THP-1 cells. Our results demonstrated that cancer-derived EVs induce an inflammatory response in non-cancerous prostate cells, while inducing an immunomodulatory phenotype in immune cells. These apparently contradictory effects are both committed to strengthening the tumour-promoting microenvironment

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Long non-coding RNA LINC01116 acts as an oncogene in prostate cancer cells through regulation of miR-744-5p/UBE2L3 axis

Cancer Cell International ◽

10.1186/s12935-021-01843-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Shengjie Yu ◽

Huihong Yu ◽

Yuanfeng Zhang ◽

Chuan Liu ◽

Weili Zhang ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Migration And Invasion ◽

Prostate Cancer Cells ◽

Cancer Cell Growth ◽

Non Coding Rna ◽

The Relationship ◽

Long Non Coding Rna

Abstract Background Long non-coding RNA (lncRNA) has been confirmed to exert a critical effect on the progression of tumors, including prostate cancer. Previous literature has demonstrated LINC01116 involves in activities of multiple cancers. However, the underlying role of LINC01116 in prostate cancer remains unclear. Methods qRT-PCR measured the expression of LINC01116 in prostate cancer cells. EdU experiment was used to detect cell proliferation. Transwell assays detected cell migration and invasion. Immunofluorescence staining and western blot assays were utilized to measure EMT progress. The binding relationship between RNAs was confirmed by a series of mechanism assays. In addition, rescue experiments were conducted to verify the relationship among RNAs. Results LINC01116 was found to be highly expressed in prostate cancer cells. Functional assays indicated that inhibition of LINC01116 could suppress cell proliferation, migration, invasion and EMT progress. Also, miR-744-5p was proven to bind with LINC01116. Moreover, UBE2L3 was verified as the target gene of miR-744-5p. In rescue assays, we discovered that inhibited miR-744-5p or overexpressed UBE2L3 could offset the suppressive influence of silencing LINC01116 on prostate cancer cells. Conclusion Our study suggested that lncRNA LINC01116 acted as an oncogene in prostate cancer and accelerated prostate cancer cell growth through regulating miR-744-5p/UBE2L3 axis.

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