The role of PIM1/PIM2 kinases in tumors of the male reproductive system.
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ABSTRACT:
SUBMITTER: Jimenez-Garcia MP
PROVIDER: S-EPMC5128923 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The PIM family of Ser/Thr kinase proteins has been implicated in tumorigenesis at different levels. PIM proteins are overexpressed in several tumor types and have been associated with chemoresistance. However, their role in hormone-dependent female tissues has not been explored, especially in the uterus, breast and ovary. We generated conditional transgenic mice with confined expression of human PIM1 or PIM2 genes in these tissues. We characterized the tumoral response to these genetic alterations corroborating their role as oncogenes since they induce hyperproliferation in all tissues and tumors in mammary gland and uterus. Furthermore, we observed a high degree of inflammatory infiltration in these tissues of transgenic mice accompanied by NFAT and mTOR activation and IL6 expression. Moreover, PIM1/2 were overexpressed in human breast, uterine and ovarian tumors, correlating with inflammatory features and stem cell markers. Our data suggest that PIM1/2 kinase overexpression provoke tissue alterations and a large IL6-dependent inflammatory response that may act synergistically during the process of tumorigenesis. The possible end-point is an increased percentage of cancer stem cells, which may be partly responsible for the therapy resistance found in tumors overexpressing PIM kinases.
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Project description:Proviral integration of Moloney virus 2 (PIM2) is a pro‑survival factor of cancer cells and a possible therapeutic target in hematological malignancies. However, the attempts at inhibiting PIM2 have yielded underwhelming results in early clinical trials on hematological malignancies. Recently, a novel pan‑PIM inhibitor, JP11646, was developed. The present study examined the utility of targeting PIM2 in multiple solid cancers and investigated the antitumor efficacy and the mechanisms of action of JP11646. When PIM2 expression was compared between normal and cancer tissues in publicly available datasets, PIM2 was found to be overexpressed in several types of solid cancers. PIM2 ectopic overexpression promoted tumor growth in in vivo xenograft breast cancer mouse models. The pan‑PIM inhibitor, JP11646, suppressed in vitro cancer cell proliferation in a concentration‑dependent manner in multiple types of cancers; a similar result was observed with siRNA‑mediated PIM2 knockdown, as well as an increased in cell apoptosis. By contrast, another pan‑PIM inhibitor, AZD1208, suppressed the expression of downstream PIM2 targets, but not PIM2 protein expression, corresponding to no apoptosis induction. As a mechanism of PIM2 protein degradation, it was found that the proteasome inhibitor, bortezomib, reversed the apoptosis induced by JP11646, suggesting that PIM2 degradation by JP11646 is proteasome‑dependent. JP11646 exhibited significant anticancer efficacy with minimal toxicities at the examined doses and schedules in multiple in vivo mice xenograft solid cancer models. On the whole, the present study demonstrates that PIM2 promotes cancer progression in solid tumors. JP11646 induces apoptosis at least partly by PIM2 protein degradation and suppresses cancer cell proliferation in vitro and in vivo. JP11646 may thus be a possible treatment strategy for multiple types of solid cancers.
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Project description:Titanium dioxide nanoparticles (TiO2-NPs) are used intensively. Thanks to their extremely small size (1-100 nm), TiO2-NPs are more absorbable by living organisms; consequently, they can cross the circulatory system and then be distributed in various organs including the reproductive organs. We have evaluated the possible toxic effect of TiO2-NPs on embryonic development and the male reproductive system using Danio rerio as an organism model. TiO2-NPs (P25, Degussa) were tested at concentrations of 1 mg/L, 2 mg/L, and 4 mg/L. TiO2-NPs did not interfere with the embryonic development of Danio rerio, however, in the male gonads the TiO2-NPs caused an alteration of the morphological/structural organization. The immunofluorescence investigation showed positivity for biomarkers of oxidative stress and sex hormone binding globulin (SHBG), both confirmed by the results of qRT-PCR. In addition, an increased expression of the gene responsible for the conversion of testosterone to dihydrotestosterone was found. Since Leydig cells are mainly involved in this activity, an increase in gene activity can be explained by the ability of TiO2-NPs to act as endocrine disruptors, and, therefore, with androgenic activity.
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Project description:BackgroundThe prognostic value of SPRY4-Intronic transcript 1 (SPRY4-IT1) in women suffering from breast carcinoma and malignant tumors of the reproductive system remains to be ascertained. Therefore, this paper attempted to assess the relationship between SPRY4-IT1 with the clinicopathological indicators and survival analysis in women suffering from breast carcinoma and malignant tumors of their reproductive organs through meta-analysis.MethodRelated literature retrieved from Cochrane Library, Ovid, Embase, PubMed, the CNKI, and the Web of Science databases were reviewed. The latest article search was updated to September 1, 2021. The outcome indicators included as effective measures in the study were hazard ratio (HR), odds ratio (OR), and 95% confidence interval (CI). The Stata 12.0 software was used to analyze the data.ResultsThe elevated SPRY4-IT1 levels were indicative of poor overall survival (OS) [HR = 2.44, 95% CI = 1.35-4.43, P < .05], and were not related to Disease-Free Survival (DFS) [HR = 1.61, 95% CI = 0.50-5.18, P = .43] in female patients suffering from malignant tumors. In terms of lymph node metastasis (LNM) for the association between long noncoding RNA SPRY4-IT1(LncRNA SPRY4-IT1) and OS, elevated LncRNA SPRY4-IT1 implied poor OS with LNM [HR = 2.79, 95% CI: 1.81-4.28, P < .001]. Based on the aspect of the LNM for the association between LncRNA SPRY4-IT1 and DFS, SPRY4-IT1 was not correlated with DFS [HR = 0.97, 95% CI: 0.73-1.28, P = .81]. SPRY4-IT1 in the TNM stage was not related to OS [HR = 1.43, 95% CI: 0.55-3.70, P = .46]. In the TNM stage, SPRY4-IT1 was not related to DFS [HR = 1.68, 95% CI: 0.92-3.06, P = .09]. SPRY4-IT1 was found to be associated with lymph node metastasis (OR = 4.15, 95% CI: 2.75-6.25, P = .000) and TNM stage (OR = 2.89, 95% CI: 1.51-7.27 P = .02). No significant correlation was noted between SPRY4-IT1 and the age of the patients (OR = 0.89, 95% CI: 0.61-1.29 P = .54).ConclusionsThus, this study provides evidence-based medical evidence for the target treatment of female breast carcinoma and malignant tumors of the reproductive system. The elevated level of SPRY4-IT1 was associated with poor prognosis of female breast cancer patients and of those having malignant tumors in their reproductive organs. In addition, the SPRY4-IT1 expression was also associated with the disease progression and metastasis.
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Project description:The elderly males undergo degenerative fertility and testicular endocrine function that jeopardize the reproductive health and well-being. However, the mechanisms underlying reproductive aging are unclear. Here, we tried to address this by investigating the phenotypes and transcriptomes of seven regions of the male mouse reproductive tract: the testis, efferent ductules, initial segment, caput, corpus and cauda epididymidis, and vas deferens, in adult (3 months) and aged (21 months) mice. Quantitative PCR, immunohistochemistry, immunofluorescent staining, and enzyme-linked immunosorbent assay were performed for the analysis of gene expression in mice, human tissues, and semen samples. Aged male mice showed both systematic and reproductive changes, and remarkable histological changes were detected in the testis and proximal epididymis. Transcriptomes of the male reproductive tract were mapped, and a series of region-specific genes were identified and validated in mouse and/or human tissues, including Protamine 1 (Prm2), ADAM metallopeptidase domain 28 (Adam28), Ribonuclease A family member 13 (Rnase13), WAP four-disulfide core domain 13 (Wfdc13), and Wfdc9. Meanwhile, age-related transcriptome changes of different regions of the male reproductive tract were characterized. Notably, increased immune response was functionally related to the male reproductive aging, especially the T cell activation. An immune response-associated factor, phospholipase A2 group IID (Pla2g2d), was identified as a potential biomarker for reproductive aging in mice. And the PLA2G2D level in human seminal plasma surged at approximately 35 years of age. Furthermore, we highlighted Protein tyrosine phosphatase receptor type C (Ptprc), Lymphocyte protein tyrosine kinase (Lck), Microtubule associated protein tau (Mapt), and Interferon induced protein with tetratricopeptide repeats 3 (Ifit3) as critical molecules in the aging of initial segment, caput, caput, and cauda epididymidis, respectively. This study provides an RNA-seq resource for the male reproductive system during aging in mice, and is expected to improve our understanding of male reproductive aging and infertility.
| S-EPMC8861499 | biostudies-literature
Project description:BackgroundAngiotensin-converting enzyme II (ACE2), a receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) to enter host cells, is widely expressed in testes and prostate tissues. The testis and prostate produce semen. At present, there are contradictory reports about whether SARS-CoV-2 can exist in the semen of infected men.ObjectiveTo provide a comprehensive overview of the topic of whether COVID-19 can impact on male reproductive system.MethodsWe reviewed the relevant publications on the possible impact of Coronavirus Disease 2019 (COVID-19) on male reproductive system and summarized the latest and most important research results so far. Literature published in English from December 2019 to January 31, 2021 regarding the existence of SARS-CoV-2 in semen, testis, and prostatic fluid and the effects of COVID-19 on male reproductive were included.ResultsWe identified 28 related studies, only one of which reported the presence of SARS-CoV-2 in semen. The study found that the semen quality of patients with moderate infection was lower than that of patients with mild infection and healthy controls. The impaired semen quality may be related to fever and inflammation. Pathological analysis of the testis/epididymis showed that SARS-CoV-2 viral particles were positive in 10 testicular samples, and the spermatogenic function of the testis was impaired. All 94 expressed prostatic secretion (EPS) samples were negative for SARS-CoV-2 RNA.ConclusionThe likelihood of SARS-CoV-2 in the semen of COVID-19 patients is very small, and semen should rarely be regarded as a carrier of SARS-CoV-2 genetic material. However, COVID-19 may cause testicular spermatogenic dysfunction via immune or inflammatory reactions. Long-term follow-up is needed for COVID-19 male patients and fetuses conceived during the father's infection period.
| S-EPMC8190708 | biostudies-literature