Exploring the role of PRDX4 in the development of uterine corpus endometrial carcinoma.

Peroxicedoxin 4 (PRDX4), a member of the peroxicedoxins (PRDXs), has been reported in many cancer-related studies, but its role in uterine corpus endometrial carcinoma (UCEC) is not fully understood. In the present study, we found that PRDX4 was highly expressed in UCEC tissues and cell lines through the combination of bioinformatics analysis and experiments, and elevated PRDX4 levels were associated with poor prognosis. Knockdown of PRDX4 significantly blocked the proliferation and migration of the UCEC cell line Ishikawa and reduced degree of cell confluence. These findings highlight the oncogenic role of PRDX4 in UCEC. In addition, genes that interact with PRDX4 in UCEC were MT-ATP8, PBK, and PDIA6, and we speculated that these genes interacted with each other to promote disease progression in UCEC. Thus, PRDX4 is a potential diagnostic biomarker for UCEC, and targeting PRDX4 may be a potential therapeutic strategy for patients with UCEC.

[Corrigendum] BMI­1 promotes invasion and metastasis in endometrial adenocarcinoma and is a poor prognostic factor.

Following the publication of the above paper, an interested reader drew to the authors' attention that, in Fig. 5 on p. 1637, the data panel selected to represent the 'Ishikawa/+BMI­1 siRNA/Invasion' experiment in Fig. 5A appeared to overlap with the data shown for the 'JEC/+BMI­1 siRNA/Migration' panel in Fig. 5C, such that they were potentially derived from the same original source. The authors have re­examined their original data, and realize that the data panel selected for the 'Ishikawa/+BMI­1 siRNA/Invasion' experiment in Fig. 5A was inadvertently selected incorrectly. The corrected version of Fig. 5, showing the correct data for the 'Ishikawa/+BMI­1 siRNA/Invasion' experiment in Fig. 5A, is shown below. Note that this error did not affect the overall conclusions reported in the study. The authors are grateful to the Editor of Oncology Reports for granting them the opportunity to publish this Corrigendum; furthermore, they apologize for any inconvenience caused to the readership of the Journal. [Oncology Reports 43: 1630­1640, 2020; DOI: 10.3892/or.2020.7539].

A correlation study of adhesion G protein-coupled receptors as potential therapeutic targets in Uterine Corpus Endometrial cancer.

BACKGROUND: Adhesion G protein-coupled receptors (adhesion GPCRs), as a member of the G protein-coupled receptors (GPCRs) superfamily, have gradually entered the field of vision of researchers. The structure, function, and involvement of adhesion GPCRs in cancer development have been discussed in a series of papers. Uterine Corpus Endometrial Carcinoma (UCEC) isa malignanttumorofendometrium epithelial, whichis alsooneofthemostcommonfemalereproductivesystemtumors, but there are few pieces of research related to adhesion GPCRs in UCEC. METHODOLOGY: In the current study, the UALCAN, GEPIA, Kaplan-Meier Plotter, MethSurv, SurvivalMeth, cBioPortal, String, GeneMANIA, DAVID, TRRUST, and Timer databases were used to examine the expression patterns and probable roles of adhesion GPCR family in UCEC. RESULTS: The expression levels of ADGRC1, ADGRC3, ADGRE1, ADGRF1, ADGRF2, ADGRF3, ADGRF4, ADGRG1, ADGRG5, ADGRG7, and ADGRV1 were significantly elevated in UCEC tissues, and the expression of ADGRC3 and ADGRF1 was significantly correlated with the pathological stage of UCEC. In patients with UCEC, ADGRA3, ADGRB1, ADGRB2, ADGRB3, ADGRC3, ADGRD2, ADGRF1, ADGRF2, ADGRF4, ADGRG1, ADGRG2, ADGRG4, ADGRG6, ADGRG7, ADGRL1, ADGRL2, and ADGRL3 had played important roles in patients' overall survival (OS), with a high expression suggesting shorter OS; while high levels of ADGRC2, ADGRD2, ADGRG7, and ADGRL2 suggested lower relapse-freesurvival (RFS). Furthermore, the prognostic value of the adhesion GPCRs gene individual CpG, as well as DNA methylation, was also analyzed; however, DNA methylation profiling demonstrated no significant correlation between the methylation level of adhesion GPCRs and the prognosis. The neighbor gene interaction analysis and enrichment analysis were also implemented to detect the possible mechanism. In addition, we found a correlation between the adhesion GPCRs and immune infiltrating cells, and the Cox proportional risk model of adhesion GPCRs with six immune cells showed that ADGRA1, ADGRF1, and ADGRG3 were closely connected with the clinical manifestations of UCEC patients. CONCLUSION: The adhesion GPCRs, especially ADGRF1, might be used as immunotherapeutic targets and prognostic markers of UCEC.

Polystyrene microplastics induce blood-testis barrier disruption regulated by the MAPK-Nrf2 signaling pathway in rats.

As a persistent pollutant, microplastics (MPs) have been reported to induce sperm quantity decrease in mice. However, the related mechanism remains obscure. Therefore, this study is intended to explore the effects of polystyrene microplastics (PS-MPs) on male reproduction and its related mechanism of blood-testis barrier (BTB) impairment. Thirty-two adult male Wistar rats were divided randomly into four groups fed with PS-MPs for 90 days at doses of 0 mg/day (control group), 0.015 mg/day, 0.15 mg/day, and 1.5 mg/day, respectively. The present results have shown that PS-MP exposure led to the damage of seminiferous tubule, resulted in apoptosis of spermatogenic cells, and decreased the motility and concentration of sperm, while the abnormality of sperm was elevated. Meanwhile, PS-MPs could induce oxidative stress and activate the p38 MAPK pathway and thus deplete the nuclear factor erythroid-2 related factor 2 (Nrf2). Noteworthily, PS-MPs led to the BTB-related protein expression decrease. All these results demonstrated that PS-MP exposure may lead to the destruction of BTB integrity and the apoptosis of spermatogenic cells through the activation of the MAPK-Nrf2 pathway. The current study provided novelty evidence for elucidating the effects of PS-MPs on male reproductive toxicity and its potential mechanism.

Decreased Expression of Peroxiredoxin in Patients with Ovarian Endometriosis Cysts.

BACKGROUND: Endometriosis (EMT) is a common occurrence in women of reproductive age. Since oxidative stress has been associated with the development and/or progression of the disease, the present study was conducted to detect the expression of peroxiredoxin (PRX) isoforms, including PRX1, PRX2, and PRX3. METHODS: Fifty-two patients with ovarian endometriosis cysts and 47 controls were included in the study. Serum levels of PRXs were detected by enzyme-linked immunosorbent assay, and the expression of PRX in the endometrium was examined by immunohistochemistry. RESULTS: Serum PRX1, PRX2, and PRX3 were significantly lower in EMT patients than in controls. The expression of the three isoforms was significantly decreased in ectopic endometrium compared to that in eutopic or control endometrium. There was no difference in PRX expression between eutopic endometrium of EMT patients and control endometrium, and no association was found between serum PRX levels and immunostaining scores. CONCLUSION: Our results are the first report that PRXs are downregulated in EMT patients, which suggests that PRXs are involved in the oxidative state of the disease.

BMI­1 promotes invasion and metastasis in endometrial adenocarcinoma and is a poor prognostic factor.

Endometrial adenocarcinoma is one of the most common types of gynecological malignancies and its incidence and mortality rates are increasing. Due to tumor recurrence and metastasis, the overall five­year survival rate of patients with endometrial adenocarcinoma is shortened. The aim of the present was to investigate the role of the polycomb group protein B­lymphoma Mo­MLV insertion region 1 (BMI­1) in the invasion, metastasis and the epithelial­mesenchymal transition (EMT) of endometrial adenocarcinoma cells, as well its effects on the prognosis of patients with endometrial adenocarcinoma. Immunohistochemistry was used to examine the expression profile of BMI­1 in normal and endometrial adenocarcinoma tissues. Western blotting was used to examine the expression levels of BMI­1 and EMT markers. Kaplan­Meier plots and a Cox proportional hazards model were used to assess the overall survival. MTT cell viability assays were used to detect the proliferation of endometrial cancer cells. Transwell assays were used to examine cell migration and invasion. Small interfering RNA was used to downregulate BMI­1 expression levels, to study its effect on EMT. Immunohistochemical and clinicopathological analyses showed that BMI­1 expression was increased in endometrial adenocarcinoma tissue compared with the normal endometrial tissue (P<0.05). The increased expression levels of BMI­1 were closely associated with stage, myometrial invasion and lymph node metastasis (P<0.05). Kaplan­Meier plots and a Cox proportional hazards model showed that increased BMI­1 expression was associated with a less favorable prognosis [P=0.040, hazards ratio (HR)=1.596] and was associated with late­stage adenocarcinoma (P=0.006, HR=1.670). Myometrial invasion (P=0.006, HR=1.509) and lymph node metastasis (P=0.004, HR=1.703) were determined to predict a less favorable prognosis. Downregulation of BMI­1 reduced migration and invasion in endometrial cancer cells in vivo. It was also found that downregulation of BMI­1 increased the expression levels of the epithelial markers E­cadherin and keratin, and decreased the expression levels of the mesenchymal markers N­cadherin, vimentin and the downstream transcription factor, Slug. In conclusion, BMI­1 expression was correlated with tumor invasion and metastasis, contributing to deep myometrial invasion and lymph node metastasis, and was a poor prognostic factor for endometrial adenocarcinoma.

Plasma level of peroxiredoxin 3 in patients with polycystic ovarian syndrome.

BACKGROUND: As a member of peroxiredoxin (PRX) family, PRX3 is predominantly located in mitochondria and plays an important role of free radical scavenging. Since a body of evidence demonstrated the involvement of PRX3 in insulin secretion, insulin sensitivity, and glucose metabolism, the present study was conducted to investigate the role of PRX3 in the pathogenesis of polycystic ovarian syndrome (PCOS) featured in insulin resistance. METHODS: Enzyme-linked immunosorbent assay was performed to detect plasma PRX3 in PCOS patients and control subjects. Levels of reactive oxygen species (ROS) and oxidized PRXs were detected in mouse islet cells treated with gradient glucose. RESULTS: We did not find significant difference of fasting plasma PRX3 between PCOS patients and controls. No association was noticed between fasting plasma PRX3 and fasting plasma glucose or insulin. After oral glucose tolerance test (OGTT), PCOS patients showed higher levels of both glucose and insulin as compared to controls. The plasma level of PRX3 was significantly increased at 2 h and began to fall back at 3 h of OGTT. There was a one-hour time lag of peak values between plasma PRX3 and insulin, and the plasma PRX3 at 2 h was positively correlated with the insulin level at 1 h of OGTT of PCOS patients. In addition, the level of ROS was significantly elevated at 1 h and oxidized PRX3 was increased dramatically at 2 h of 16.7mM glucose stimulation in mouse islet cells. CONCLUSION: It seems that PRX3 does not show its antioxidant function under baseline conditions. Instead, PRX3 responds to oxidative stress induced by rapid increase of insulin and glucose in patients with PCOS.

The association of plasma peroxiredoxin 3 with insulin in pregnant women.

Peroxiredoxin 3 (PRX3) is predominantly located in mitochondria and plays a major role in scavenging hydrogen peroxide of mitochondria. In the present study, we detected plasma PRX3 in pregnant women receiving oral glucose tolerance test at 24-28 gestational weeks. Plasma PRX3 was significantly increased about 1 h later than insulin secretion. In vitro detection of PRX3 in mouse islet cells showed up-regulation by more than 2-fold at 1 h and reached its top at 2 h of glucose stimulation, and the PRX3 level in cultured mediums was concomitantly elevated in a glucose concentration-dependent manner. In addition, both fasting plasma insulin and PRX3 were significantly higher in the subjects of term pregnancy as compared to that at 24-28 gestational weeks, and there was a positive correlation between plasma PRX3 and insulin. Our results indicate that PRX3 plays an active role in the response to insulin release. The positive association of plasma PRX3 and insulin suggest PRX3 to be a potential indicator of high insulin resistance.

The Relevance of Mammalian Peroxiredoxins to the Gametogenesis, Embryogenesis, and Pregnancy Outcomes.

Peroxiredoxin (PRX) defines a family that provides antioxidant defense in different cell types by removing reactive oxygen species (ROS) through conserved active cysteines, with the support of other types of antioxidants such as thioredoxin, glutaredoxin, and glutathione peroxidase. By regulation of intracellular ROS levels, the mammalian PRXs influence a variety of reproductive processes including gamete maturation, fertilization, and embryo development. Experimental mice lacking PRXs developed normally, but some showed accelerated decrease in fertility with aging, suggesting that deficiency of PRXs did not have lethal consequences for reproduction. The aim of this review is to summarize the role of mammalian PRXs in the reproductive performance.

The Potential Role of Probiotics in Cancer Prevention and Treatment.

The human gut microbiota has a significant effect on many aspects of human physiology such as metabolism, nutrient absorption, and immune function. Imbalance of the microbiota has been implicated in many disorders including inflammatory bowel disease, obesity, asthma, psychiatric illnesses, and cancers. As a kind of functional foods, probiotics have been shown to play a protective role against cancer development in animal models. Clinical application of probiotics indicated that some probiotic strains could diminish the incidence of postoperative inflammation in cancer patients. Chemotherapy or radiotherapy-related diarrhea was relieved in patients who were administered oral probiotics. The present review summarizes the up-to-date studies on probiotic effects and the underlying mechanisms related to cancer. At present, it is commonly accepted that most commercial probiotic products are generally safe and can improve the health of the host. By modulating intestinal microbiota and immune response, some strains of probiotics can be used as an adjuvant for cancer prevention or/and treatment.

Featured Article: Accelerated decline of physical strength in peroxiredoxin-3 knockout mice.

As a member of peroxiredoxin family, peroxiredoxin-3 plays a major role in the control of mitochondrial level of reactive oxygen species. During the breeding of experimental mice, we noticed that the peroxiredoxin-3 knockout mice were listless with aging. In the present study, we compared the swimming exercise performance and oxidative status between peroxiredoxin-3 knockout mice (n = 15) and wild-type littermates (n = 15). At the age of 10 months, the physical strength of peroxiredoxin-3 knockout mice was much lower than the wild-type littermates. Increased oxidative damage and decreased mitochondrial DNA copy number of the animal skeletal muscles were observed in peroxiredoxin-3 knockout mice as compared to that in the wild-type littermates. In addition, we found increased apoptotic cells in the brains of peroxiredoxin-3 knockout mice. Our results suggest that the deficiency of peroxiredoxin-3 induces accelerated oxidative stress and mitochondrial impairment, resulting in the decrease of energy supply and cellular activities. Peroxiredoxin-3 might be involved in the inhibition of aging process.

The functional role of peroxiredoxin 3 in reactive oxygen species, apoptosis, and chemoresistance of cancer cells.

PURPOSE: The mammalian peroxiredoxin (PRX) family contains six members that provide antioxidant defense in different cell types by removing reactive oxygen species (ROS) through conserved active cysteines. Different from other members, PRX3 is predominantly located in mitochondria, a major apoptosis mediator. The purpose of this review is to summarize the findings on PRX3 concerning its role in ROS removal, apoptosis, and chemoresistance of cancer cells. METHODS: The relevant literature from PubMed and Medline databases is reviewed in this article (1994-2014). RESULTS: Because of fast growth and relatively low supply of oxygen in cancer cells, ROS production from mitochondria is exaggerated to an extent that overwhelms cellular antioxidant defenses resulting in oxidative stress. As an active responder to oxidative stress, PRX3 is accordingly up-regulated in cancer cells to remove cellular ROS and inhibit apoptosis, which provides a favorable microenvironment for cell proliferation. CONCLUSION: Since most of chemotherapy or radiotherapy for cancers is through ROS increase and apoptotic induction, PRX3 might be involved in the chemotherapeutic resistance of cancers.

HPV16 early gene E5 specifically reduces miRNA-196a in cervical cancer cells.

High-risk human papillomavirus (HPV) type 16, which is responsible for greater than 50% of cervical cancer cases, is the most prevalent and lethal HPV type. However, the molecular mechanisms of cervical carcinogenesis remain elusive, particularly the early steps of HPV infection that may transform normal cervical epithelium into a pre-neoplastic state. Here, we report that a group of microRNAs (microRNAs) were aberrantly decreased in HPV16-positive normal cervical tissues, and these groups of microRNAs are further reduced in cervical carcinoma. Among these miRNAs, miR196a expression is the most reduced in HPV16-infected tissues. Interestingly, miR196a expression is low in HPV16-positive cervical cancer cell lines but high in HPV16-negative cervical cancer cell lines. Furthermore, we found that only HPV16 early gene E5 specifically down-regulated miRNA196a in the cervical cancer cell lines. In addition, HoxB8, a known miR196a target gene, is up-regulated in the HPV16 cervical carcinoma cell line but not in HPV18 cervical cancer cell lines. Various doses of miR196a affected cervical cancer cell proliferation and apoptosis. Altogether, these results suggested that HPV16 E5 specifically down-regulates miR196a upon infection of the human cervix and initiates the transformation of normal cervix cells to cervical carcinoma.

Anti-apoptotic role of peroxiredoxin III in cervical cancer cells.

As a member of peroxiredoxin (Prx) family, PrxIII is predominantly located in mitochondria and plays an important role as a scavenger of reactive oxygen species (ROS). Since previous reports demonstrated over-expression of PrxIII in cervical cancer, we conducted the present study to investigate the significance of PrxIII in cervical cancer development and/or progression. Cervical cancer cells were cultured from tissues derived from cervical cancer patients. After successful knockdown of PrxIII expression by small interfering RNA, we evaluated ROS level, viable cell number, and apoptosis of cervical cancer cells along with the culture time. The production of ROS was increased in cervical cancer cells as compared with normal cervical epithelia. Knockdown of PrxIII expression induced up-regulation of other Prx members including PrxI, PrxII, and PrxV. ROS level was higher in down-regulated cervical cancer cells than in controls and the difference was increasing with culture time. We also observed increased apoptosis and decreased viable cell number in down-regulated cervical cancer cells. Our results suggest that PrxIII is an indispensable ROS scavenger, which protects tumor cells against oxidative damage and subsequent apoptosis.

Peroxiredoxin 3 is a novel marker for cell proliferation in cervical cancer.

Although peroxiredoxin 3 (Prx3) has been reported to be involved in cervical cancer (CC) carcinogenesis, the significance of Prx3 in CC progression remains unclear. The present study was conducted to investigate the expression features of Prx3 to better understand the mechanism of tumor growth and invasion. Sixty-eight patients with invasive squamous cervical cancer were included in the present study. The status of human papillomavirus (HPV) infection was detected by hybridization and quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemistry was performed on paraffin-embedded sections using monoclonal antibodies against Prx3 and Ki67. All samples were positive for high-risk HPV, among which fifty-six samples were positive for HPV16, seven for HPV18 and five for HPV33. The expression of HPV16 E6/E7 was significantly higher in cancer areas compared to the adjacent normal epithelial tissuses. The positive cells for Prx3 and Ki67 were significantly higher in cancer cells compared to normal epitheliums and the staining pattern of Prx3 was consistent with that of Ki67 (Pearson's correlation coefficient was 0.801, P= 0.000). The upregulation of Prx3 might be a protective response to oxidative stress in the cancer microenvironment. The expression consistency of Prx3 and Ki67 suggests Prx3 to be a potential marker for cell proliferation of CC.

Role of peroxiredoxin III in the pathogenesis of pre-eclampsia as evidenced in mice.

As a member of peroxiredoxin (Prx) family, PrxIII has been demonstrated to play an important role in scavenging intracellular reactive oxygen species (ROS). Since PrxIII knockout mice exhibited oxidative stress in placentas resembling pathophysiologic changes in placentas of human pre-eclampsia, we measured blood pressure through the carotid artery and detected oxidative status by Western blotting in pregnant mice. We did not notice hypertension in pregnant PrxIII knockout mice as compared with wild-type littermates, although endothelin-1 was over-expressed in PrxIII-deficient placentas. Our results indicate that PrxIII is not involved in pre-eclamptic development. Instead, PrxIII is an indispensable antioxidant in placentas where oxidative stress exists.

Peroxiredoxin III-deficiency sensitizes macrophages to oxidative stress.

As a mitochondrial scavenger of reactive oxygen species (ROS), peroxiredoxin III (PrxIII) plays an important role in regulating intracellular ROS level. We previously found that PrxIII knockout (PrxIII(-/-)) mice were more sensitive than wild-type (PrxIII(+/+)) controls to intratracheal inoculation of lipopolysaccharide (LPS), but the precise mechanism remained to be obscure. In the present study, we detected the levels of ROS and tumour necrosis factor alpha (TNF-alpha) in mouse bone-marrow-derived macrophages. LPS stimulation induced transient increase of ROS production and augmentation of TNF-alpha accumulation in PrxIII(-/-) macrophages. In addition, we observed reduced viability and increased apoptosis in PrxIII(-/-) macrophages exposed to LPS. Our results provide direct evidence that PrxIII is necessary for macrophages to protect against LPS-induced oxidative stress.

[Expression of peroxiredoxin III in cervical lesions].

OBJECTIVE: To investigate the expression feature of peroxiredoxin III in cervical lesions and to further understand the mechanism for cervical cancer development/progression. METHODS: Expression of peroxiredoxin III was immunohistochemically detected in cervical cancer. In addition, cervical epithelia were transfected with recombinant adeno-associated virus vector containing human papillomavirus 16 E6/E7 and peroxiredoxin III expression was detected by quantitative real time PCR and Western blotting. RESULTS: Peroxiredoxin III was significantly up-regulated in cervical cancer tissues. Nevertheless, expression of peroxiredoxin III remained unchanged in cervical epithelial cells after transfection. CONCLUSION: It seems that Prx III is not related to cervical cancer initiation. Up-regulation of peroxiredoxin III in cervical cancer might be an active response to oxidative stress in malignant cells, which protects against oxidatiton-induced apoptosis.

Crucial role of peroxiredoxin III in placental antioxidant defense of mice.

We observed frequent stillbirth in peroxiredoxin III (PrxIII) knockout maternal mice. Quantitative real time PCR (qRT-PCR) and Western-blot analysis revealed increased oxidative stress in placentas that were deficient in PrxIII. We did not find significant difference between PrxIII knockout maternal mice and wild-type littermates in hematological parameters, fetal number, and embryonic development. Nevertheless, we noticed enhanced expression of PrxI in erythrocytes of pregnant knockout mice. Our results provided in vivo evidence that PrxIII played a crucial role in placental antioxidant defense. Up-regulation of PrxI might provide a compensation that protected erythrocytes against oxidative damage.

Increased susceptibility of MER5 (peroxiredoxin III) knockout mice to LPS-induced oxidative stress.

MER5 (also called peroxiredoxin III, PrxIII) is a member of peroxiredoxin family that has antioxidant activity. The present study was performed to investigate its in vivo function using MER5 knockout mice. MER5 knockout mice were born in normal frequency and could grow to maturity, but we found that intracellular ROS levels are significantly higher in the macrophages of the knockout mice. We examined roles of MER5 function for the oxidative stress responses by intratracheal inoculation of lipopolysaccharide (LPS) to the mice. Lung inflammation such as inflammatory cell infiltration and airway wall thickening was more severely detected in the knockout mice. At the same time, oxidative damage on DNA and proteins was more strongly detected in lung tissues of the knockout mice, including 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation and protein carbonylation. The degrees of lung inflammation and oxidative damage were positively related with LPS doses. Our results indicate that MER5 knockout mice accumulated higher intracellular ROS levels, which cause LPS-induced lung injury more severely, and thus, suggested that MER5 acts as an important scavenger of reactive oxygen species (ROS) under oxidative stress.