Artificial intelligence enables precision diagnosis of cervical cytology grades and cervical cancer.

Cervical cancer is a significant global health issue, its prevalence and prognosis highlighting the importance of early screening for effective prevention. This research aimed to create and validate an artificial intelligence cervical cancer screening (AICCS) system for grading cervical cytology. The AICCS system was trained and validated using various datasets, including retrospective, prospective, and randomized observational trial data, involving a total of 16,056 participants. It utilized two artificial intelligence (AI) models: one for detecting cells at the patch-level and another for classifying whole-slide image (WSIs). The AICCS consistently showed high accuracy in predicting cytology grades across different datasets. In the prospective assessment, it achieved an area under curve (AUC) of 0.947, a sensitivity of 0.946, a specificity of 0.890, and an accuracy of 0.892. Remarkably, the randomized observational trial revealed that the AICCS-assisted cytopathologists had a significantly higher AUC, specificity, and accuracy than cytopathologists alone, with a notable 13.3% enhancement in sensitivity. Thus, AICCS holds promise as an additional tool for accurate and efficient cervical cancer screening.

Long non-coding RNA JPX promotes endometrial carcinoma progression via janus kinase 2/signal transducer and activator of transcription 3.

Introduction: Although LncRNA JPX has been linked to a number of malignancies, it is yet unknown how it relates to endometrial carcinoma (EC). Investigating the expression, functional activities, and underlying molecular processes of lncRNA JPX in EC was the goal of this work. Methods: RT-qPCR was used to examine the differences in lncRNA/microRNA (miRNA, miR)/mRNA expression between normal cervical and EC tissues or cells. Cell Counting Kit-8, flow cytometry, and transwell were used to evaluate the association between lncRNA JPX/miR-140-3p/phosphoinositide-3-kinase catalytic subunit α (PIK3CA) in Ishikawa and JEC cell lines. The impact of JPX on the downstream janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling pathway was investigated using Western blot analysis. Results: When comparing EC tissues to nearby normal tissues, JPX expression is markedly increased in EC tissues, with greater expression in advanced-stage EC. Furthermore, compared to normal epithelial cells, EC cell lines have higher levels of JPX expression. In Ishikawa and JEC endometrial cancer cell lines, we used siRNA-mediated suppression of JPX to find lower cell viability, increased apoptosis, cell cycle arrest, and reduced migration and invasion. We next verified that miR-140-3p binds to downstream target cells to impede the transcription and translation of PIK3CA, which in turn prevents the growth of Ishikawa and JEC cells. JPX functions as a ceRNA to adsorb miR-140-3p. This procedure required controlling JAK2/STAT3, a downstream signal. Conclusion: JPX enhances the development of Ishikawa and JEC cells and activates downstream JAK2/STAT3 signal transduction via the miR-140-3p/PIK3CA axis, offering a possible therapeutic target for the treatment of EC.

PAX2 is regulated by estrogen/progesterone through promoter methylation in endometrioid adenocarcinoma and has an important role in carcinogenesis via the AKT/mTOR signaling pathway.

Endometrioid adenocarcinoma (EEC) is one of the most common cancers of the female reproductive system. In recent years, much emphasis has been placed on early diagnosis and treatment. PAX2 (Paired box 2) inactivation is reportedly an important biomarker for endometrioid intraepithelial neoplasia (EIN) and EEC. However, the role of PAX2 in EEC carcinogenesis remains unclear. PAX2 expression and associated clinical characteristics were analyzed via The Cancer Genome Atlas, Gene Expression Omnibus, and Cancer Cell Line Encyclopedia databases and clinical paired EIN/EEC tissue samples. Bioinformatic analysis was conducted to identify the putative molecular function and mechanism of PAX2. Cell proliferation, colony formation, cell migration, and invasion assays in vitro, and mouse xenograft models were utilized to study the biological functions of PAX2 in vivo. Pyrosequencing and the demethylating drug 5-Aza-dc were used to verify promoter methylation in clinical tissues and cell lines, respectively. The mechanism underlying the regulatory effect of estrogen (E2) and progesterone (P4) on PAX2 expression was investigated by receptor block assay and double luciferase reporter assay. PAX2 expression was found to be significantly downregulated in EIN and EEC tissues, its overexpression inhibited EEC cell malignant behaviors in vivo and in vitro and inhibited the AKT/mTOR signaling pathway. PAX2 inactivation in EEC was related to promoter methylation, and its expression was regulated by E2 and P4 through their receptors via promoter methylation. Our findings elucidated the expression and function of PAX2 in EEC and have provided hitherto undocumented evidence of the underlying molecular mechanisms. PAX2 expression is suppressed by estrogen prompting its methylation through estrogen receptor. Furthermore, PAX2 regulates the AKT/mTOR signaling pathway to influence EEC progression. © 2024 The Pathological Society of Great Britain and Ireland.

Clinical effect of wumei bolus on ulcerative colitis: A meta-analysis.

Wumei Bolus is a traditional Chinese medicine prescription, first appeared in Shennong Bencao Jing. Modern pharmacology believes that Wumei Bolus has antibacterial, antitussive, sedative, antiviral and anti-tumor effects, and plays a therapeutic role by acting on multi-target/multi-pathway. Moreover, it has great advantages in digestive system diseases, such as repairing the damaged gastrointestinal mucosa and improving the inflammatory environment. Aim of the study: This review aimed to evaluate the efficacy and safety of prescriptions based on the Wumei Bolus treating ulcerative colitis (UC). Materials and methods: In this meta-analysis, we searched CNKI, Wanfang Database, VIP, Pubmed, Web of Science (WOS) with language restrictions of Chinese and English for articles published from the establishment of the database to Dec 2022. This meta-analysis controlled randomized controlled trials (RCTs) assessing the efficacy and safety of Wumei Bolus against ulcerative colitis and using RevMan 5.4 and Stata 15.0to analyze information from the compliant studies. Results: The search incorporated 3145 results (1617 cases assigned into Wumei Bolus group and 1528 cases assigned into control group), from which 37 studies fulfilled our inclusion criteria and were included. The outcomes of this meta-analysis showed that compared to the control group, the Experiment group was significantly more effective (RR = 1.24，95%CI [1.20，1.28])and lower adverse reactions (RR = 0.32, 95%CI [0.20, 0.53]). According to the subgroup analysis, The results showed that the RR = 1.23 and 95%CI [1.16, 1.30] in the group treated with Wumei Bolus alone and the group treated with Western medicine with RR = 1.25 and 95%CI [1.20, 1.30], indicating that the efficacy of Wumei Bolus in the treatment of UC was better and the difference was statistically significant (P < 0.00001). The results showed that compared with the control group, the experimental group had more advantages in reducing inflammatory factors whether TNF-α or IL-8 (TNF-α:SMD = -4.44, 95%CI [-5.75, -3.14]; IL-8: SMD = -3.02, 95%CI [-4.06, -1.97]) and improving TCM symptoms and reduced TCM syndrome points (SMD = -3.82, 95%CI [-4.30, -3.34]). There was significant association of the basic treatment of Wumei Bolus improving clinical efficacy, reducing serum pro-inflammatory factors, improving symptoms, and reducing adverse reactions in UC patients. These results were statistically significant (P < 0.00001). Conclusions: The prescriptions based on the Wumei Bolus is greatly related to reducing serum pro-inflammatory factors, improving symptoms, improving clinical efficacy and reducing adverse reactions in the treatment of UC compared to conventional western medicine and improve the total clinical effective rate.

CIN grades possessing different HPV RNA location patterns and RNAscope is helpful tool for distinguishing squamous intraepithelial lesions in difficult cervical cases.

BACKGROUND AND OBJECTIVES: The precise grading and characterization of cervical intraepithelial neoplasia (CIN) has been the focus of pathologists for a long time. This study aimed to explore known strategies for the grading of CINs. METHODS: After routine H&E review, 85 lesions graded CIN 1, 2, or 3 were investigated primarily by HPV RNAscope to detect HR-HPV and LR-HPV, in combination with an HPV-DNA test and P16/Ki67 immunohistochemistry (IHC). Then, the 85 cases were divided into a control group (49 cases) and a test group (36 cases). The former consisted of cases with consistency between morphology, HPV DNA detection and P16/Ki67 IHC. We used them to evaluate HPV RNA distribution patterns in CINs of different grades. The latter were ambiguous cases in which pathologists could not confirm the diagnosis because of inconsistencies between morphology, HPV DNA detection and P16/Ki67 IHC. We reassessed them by comparison to the pattern in the control group. RESULTS: The expression patterns of HPV mRNA signals were different in different CIN lesions. LSIL/CIN1 lesions were mostly expressed in superficial epithelium with diffuse clustered nuclear or cytoplasmic staining; HSIL/CIN2 were characterised by nuclear/cytoplasmic punctate or diffuse cluster nuclear staining in the mid-surface layer, and scattered nuclear/cytoplasmic punctate staining in basal and parabasal cells; whereas HSIL/CIN3 showed full-thickness nucleus/cytoplasmic scattered staining with a punctate pattern. According to the staining pattern, we corrected the diagnosis of 22 cases (22/36, 61.1%). CONCLUSION: Because of its distinct location pattern, HPV RNAscope has obvious advantages over the HPV-DNA test, and combined with P16/Ki67 IHC, it can help pathologists correctly grade CIN. In addition, it can effectively discriminate true CIN from normal or CIN mimic lesions, such as immature squamous metaplasia, atrophy, and inflammatory/reactive changes. Therefore, HPV RNAscope is a valuable auxiliary diagnostic test to avoid the overtreatment and undertreatment of CIN lesions.

Promotive role of IRF7 in ferroptosis of colonic epithelial cells in ulcerative colitis by the miR-375-3p/SLC11A2 axis.

Ferroptosis is implicated in the progression of ulcerative colitis (UC), and interferon regulatory factor 7 (IRF7) contributes to cell death. This study probed the mechanism of IRF7 in ferroptosis of colonic epithelial cells (ECs) in mice with dextran sodium sulfate (DSS)-induced UC. The UC mouse model and the in vitro ferroptosis model were respectively established by DSS feeding and the treatment with FIN56 (a ferroptosis inducer). Results of quantitative real-time polymerase chain reaction and western blotting revealed the upregulation of IRF7 and solute carrier family 11 member 2 (SLC11A2/NRAMP2/DMT1) and the downregulation of microRNA (miR)-375-3p in DSS-treated mice and FIN56-treated ECs. Silencing of IRF7 improved the symptoms of UC in DSS-induced mice and decreased the levels of tumor necrosis factor α, interleukin 6, monocyte chemoattractant protein 1, and interleukin 1ß, reactive oxygen species, iron ions, lipid peroxidation, and increased glutathione and glutathione peroxidase 4. Chromatin immunoprecipitation and dual-luciferase assays showed that binding of IRF7 to the miR-375-3p promoter inhibited miR-375-3p expression, and miR-375-3p suppressed SLC11A2 transcription. The rescue experiments revealed that knockdown of miR-375-3p neutralized the role of silencing IRF7 in alleviating ferroptosis of colonic ECs. Overall, IRF7 upregulated SLC11A2 transcription by inhibiting miR-375-3p expression, thereby prompting ferroptosis of colonic ECs and UC progression in DSS-treated mice.

Tricresyl phosphate inhibits fertilization in Japanese medaka (Oryzias latipes): Emphasizing metabolic toxicity.

As tricresyl phosphate (TCrP) is commonly found in global water sources, its potential reproductive toxicity to fish is of increasing concern. Japanese medaka larvae were exposed to TCrP at 657.9, 1,511, and 4042 ng/L for 100 days. We identified significant fertilization inhibition (6.9%-12.8%) in all exposure groups. Intersex was significantly induced at 4042 ng/L, with an incidence of 22.0%. TCrP exposure also caused dilation of the efferent duct in the testes with maximum duct widths of 83.3, 93.2, and 149.7 µm in the 657.9, 1,511, and 4042 ng/L exposure groups, respectively. These widths were all significantly larger than that observed in the control group (37.7 µm) and likely contributed substantially to fertilization inhibition. The TCrP metabolites 4-OH-MDTP and 3-OH-MDTP, were detected at high concentrations in the liver and elicited 5.8-fold and 5.3-fold greater androgen receptor antagonistic activity than that elicited by TCrP (39.8 µM), which may explain the intersex observed in low exposure groups. 4-OH-MDTP and 3-OH-MDTP elicited anti-estrogenic activities by blocking the estrogen receptor, and the concentrations at which its responses were equal to the IC20 of tamoxifen were 16.1 µM and 18.9 µM, respectively, as detected using the yeast two-hybrid assay. Such anti-estrogenic activities were likely the main driver of dilation of the efferent duct. Observed adverse outcomes after exposure to TCrP all occurred under environmentally relevant concentrations, suggesting considerable ecological risk to wild fish.

UPF1 impacts on mTOR signaling pathway and autophagy in endometrioid endometrial carcinoma.

Most EEC cases are associated with activities of the mTOR pathway, which regulates protein synthesis, cell growth and autophagy. While Up-Frameshift 1(UPF1) is a key protein factor in the nonsense-mediated mRNA degradation pathway (NMD), its role in carcinogenesis of EEC remains unclear. In this study, we first evaluated the expression level of UPF1 in EEC tissues and cell lines. Then, we investigated the effect of UPF1 on cellular function and mTOR signaling pathway; these effects were further validated in vivo. Finally, its effect on autophagy was evaluated by western blot and GFP-mRFP-LC3 staining. UPF1 expression in the EEC tissue samples was significantly higher than that of matched normal tissue samples. Overexpression of UPF1 promoted migration and invasion of EEC cells. Conversely, depletion of UPF1 suppressed migration and invasion of EEC cells. In addition, overexpression of UPF1 increased the in vivo growth of our EEC xenograft tumors. Finally, UPF1 increased the activity of the mTOR/P70S6K/4EBP1 signaling pathway and inhibited autophagy in EEC cells. These findings suggest that UPF1 functions as an oncogene to promote EEC carcinogenesis. Our findings propose UPF1 as a new potential therapeutic target for EEC.

ER-positive endocervical adenocarcinoma mimicking endometrioid adenocarcinoma in morphology and immunohistochemical profile: A case report of application of HPV RNAscope detection.

RATIONALE: Usual-type endocervical adenocarcinoma (ECA), high-risk HPV associated, is the most common type of glandular carcinoma in the endocervix. Mucin-depleted usual-type ECA is 1 end of morphological lineage of usual-type ECA and morphologically may show endometrioid features, which could cause diagnostic challenge with uterine endometrioid adenocarcinoma (EEC) and primary endometrioid ECA, especially in the setting of small biopsy and endocervical curettage (ECC). PATIENT CONCERNS: A 37-year-old women presented with dyspareunia for 1 year, showing atypical glandular cell on a liquid-based Pap TCT examination and positive for HPV16 detection. ECC showed EEC in another hospital based on its "endometrioid" morphology and immunohistochemical profiles (ER/PR/PAX8 strongly positive, though p16 also strongly positive). DIAGNOSES: The specimen of hysterectomy in our hospital displayed a lesion confined to the uterine cervix showing the same morphology and immunohistochemical profiles as ECC. Finally, we successfully performed HPV RNAscope and detected high-risk human papilloma virus (HPV) E6/E7 mRNA particles in tumor cells in situ, which warranted usual-type ECA with mucin-depleted feature, a rare deviation of usual-type of ECA. INTERVENTIONS: The patient underwent total hysterectomy with lymph node dissection. OUTCOMES: To date, 14 months after surgery, the patient is well without recurrence or distant metastasis, and undergoes regular reexamination. LESSONS SUBSECTIONS: We report a rare case of mucin-depleted usual-type ECA showing overlapping morphological and immunohistochemical profiles with EEC. The pathological diagnosis was confirmed by high-risk HPV RNAscope detection which is superior than immunohistochemistry to identify usual-type ECA, warranting an important role in assisting the diagnosis of morphological vague cases.

A 4-gene signature predicts prognosis of uterine serous carcinoma.

BACKGROUND: Uterine serous carcinoma (USC) is an aggressive type of endometrial cancer that accounts for up to 40% of endometrial cancer deaths, creating an urgent need for prognostic biomarkers. METHODS: USC RNA-Seq data and corresponding patients' clinical records were obtained from The Cancer Genome Atlas and Genotype-Tissue Expression datasets. Univariate cox, Lasso, and Multivariate cox regression analyses were conducted to forge a prognostic signature. Multivariable and univariable cox regression analysis and ROC curve evaluated the prediction efficiency both in the training and testing sets. RESULTS: We uncovered 1385 genes dysregulated in 110 cases of USC tissue relative to 113 cases of normal uterine tissue. Functional enrichment analysis of these genes revealed the involvement of various cancer-related pathways in USC. A novel 4-gene signature (KRT23, CXCL1, SOX9 and ABCA10) of USC prognosis was finally forged by serial regression analyses. Overall patient survival (OS) and recurrence-free survival (RFS) were significantly lower in the high-risk group relative to the low-risk group in both the training and testing sets. The area under the ROC curve of the 4-gene signature was highest among clinicopathological features in predicting OS and RFS. The 4-gene signature was found to be an independent prognostic indicator in USC and was a superior predictor of OS in early stage of USC. CONCLUSIONS: Our findings highlight the potential of the 4-gene signature as a guide for personalized USC treatment.

MiR-200a Regulates Nasopharyngeal Carcinoma Cell Migration and Invasion by Targeting MYH10.

Nasopharyngeal carcinoma (NPC), is one of the most common malignant tumor in southern China and southeast Asia. MYH10 is a coding gene of the NMMHC-IIB protein. Previous studies have shown that MYH10 expression was up-regulated in breast cancer, glioma and meningioma. Moreover, it was targeted by miR200 family. However, no relevant studies have been found in NPC. In present study, we found in 48 NPC specimens, MYH10 level was lower in most cancer areas than that in the adjacent normal tissue. Moreover, the depletion of MYH10 can promote the migration and invasion of NPC. In addition, we demonstrated that miR-200a has the strongest regulation to MYH10 among miR-200 family. miR-200a mimics could decrease MYH10 expression, while miR-200a inhibitor increase MYH10 expression. Next, we found that miR-200a bound directly to MYH10 using Dual-luciferase reporter. Finally, it was demonstrated that siMYH10 could reverse the effect of miR-200a inhibitor on NPC cell migration and invasion. Taken together, it can be concluded that MYH10 is lowly expressed in NPC compared with adjacent tissues, and the loss of MYH10 can promote the migration and invasion of NPC cells; Among the miR-200 family, miR-200a has the strongest regulatory effect on MYH10; MYH10 is a direct target gene of miR200a, and miR200a targets MYH10 to regulate the migration and invasion of NPC cells.

Triphenyl Phosphate at Environmental Levels Retarded Ovary Development and Reduced Egg Production in Japanese Medaka (Oryzias latipes).

Since triphenyl phosphate (TPhP) elicits both antiestrogenic activities via blocking the estrogen receptor (ER) and estrogenic activity by elevating 17ß-estradiol (17ß-E2) synthesis, its adverse effect on female reproduction is uncertain. In this study, we exposed Japanese medaka to TPhP at 131, 363, and 1773 ng/L for 100 days following hatching. TPhP significantly induced ovary retardation in all exposure groups (incidence: from 11.9 to 37.8%) and reduced egg production by 38.9 and 50.9% in the 363 and 1773 ng/L exposure groups, respectively. Vitellogenin (vtg) transcription was significantly downregulated by 35.4-57.4% after TPhP exposure, explaining the ovary retardation. Considering that 17ß-E2 was only significantly decreased in the 1773 ng/L exposure group, ER antagonism could be the dominant contributor to the inhibition of vtg transcription and female reproductive toxicity of TPhP. As 4-hydroxyphenyl diphenyl phosphate, a metabolite of TPhP, was detected in livers with similar concentration [68.4-1237 ng/g lipid weight (lw)] to that of TPhP (485-1594 ng/g lw) and elicited medaka ER antagonistic activity (50% inhibitory concentration = 78.1 µM), TPhP and its metabolite should both contribute to the reproductive inhibition. We demonstrate that TPhP at environmentally relevant concentrations is toxic to female reproduction, which poses an ecological risk to wild fish at the population level.

Estrogen affects the negative feedback loop of PTENP1-miR200c to inhibit PTEN expression in the development of endometrioid endometrial carcinoma.

Endometrial carcinoma is one of the most common malignancies in the female reproductive system. It is well-known that estrogen plays an important role in the pathogenesis of endometrioid endometrial carcinoma (EEC), and induces the cancer suppressor gene PTEN deletion. However, how estrogen affects PTEN expression remains unknown. In the present study, we found in 40 EEC specimens, miR-200c level was higher in most cancer areas than that in the adjacent normal endometrium, while PTEN and PTENP1 were lower. Moreover, the expression of PTEN/PTENP1 and miR-200c also showed a converse relationship in EEC cell lines. In addition, we demonstrated that miR-200c bound directly to PTEN and PTENP1, and PTENP1 could reverse miR-200c inhibition function to PTEN using a dual-luciferase reporter and RNA binding protein immunoprecipitation (RIP) assays. Next, 17ß-estradiol (E2) treatment could improve miR-200c and drop the PTEN level, which caused a consequential increase of the phospho-PI3K-AKT pathway genes. When we stably knocked down estrogen receptor α (ERα) expression in the EEC cell line, the effects of E2 on miR-200c and PTEN declined. In addition, it was demonstrated that E2 might modulate cell proliferation, migration and invasion relying on the expression of miR-200c. Taken together, it can be concluded that estrogen improves the miR-200c level by combining with ER, PTENP1 and PTEN could be inhibited by miR-200c, and then activate the PI3K-AKT pathway. This work provided a new mechanism of EEC development and a new potential therapeutic target.

MicroRNA-183 induces epithelial-mesenchymal transition and promotes endometrial cancer cell migration and invasion in by targeting CPEB1.

The aim of this study is to evaluate the ability of microRNA-183 (miR-183) to influence epithelial-mesenchymal transition (EMT) and cell proliferation, migration, invasion, and apoptosis in endometrial cancer (EC) by targeting cytoplasmic polyadenylation element binding protein 1(CPEB1). EC tissues with matched nonmalignant tissues were collected from 208 EC patients. Ishikawa and RL95-2 cells were selected for cell experiments in vitro and each kind of cells were grouped into blank, negative control (NC), miR-183 mimic, miR-183 inhibitor, CPEB1 overexpression, and miR-183 mimic + CPEB1 overexpression groups. Expressions of miR-183, CPEB1, E-cadherin, and Vimentin were determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Cell viability, colony formation ability, migration, invasion, and apoptosis were assessed by MTT assay, clone formation assay, scratch test, Transwell assay, and flow cytometry. In vivo tumorigenesis of Ishikawa cells was evaluated by tumor formation in nude mice. The miR-183 expression was higher, but the CPEB1 expression was lower in EC tissues than in adjacent nonmalignant tissues. CPEB1 was confirmed as the target of miR-183 by dual-luciferase reporter assay. The miR-183 mimic group had increased cell viability, colony formation ability, cell invasion and migration, tumor volume and weight in nude mice, but decreased cell apoptosis when compared with the blank group. The expression of E-cadherin was down-regulate, but expression of Vimentin was up-regulate in the miR-183 mimic group in comparison with the blank group. In terms of a comparison between the blank group and CPEB1 overexpression group, the CPEB1 overexpression group had suppressed cell viability, colony formation ability, cell invasion and migration, tumor volume and weight, but increased cell apoptosis. The expression of E-cadherin was up-regulated, but the expression of Vimentin was down-regulated in the CPEB1 overexpression group in comparison with the blank group. The miR-183 mimic + CPEB1 overexpression group had higher miR-183 expression than the blank group. These findings indicate that miR-183 induces EMT, inhibits apoptosis, and promotes cell proliferation, migration, invasion, and in vivo tumorigenesis in EC by targeting CPEB1.

Retraction: The Epstein-Barr Virus-encoded miR-BART22 targets MAP3K5 to promote host cell proliferative and invasive abilities in nasopharyngeal carcinoma.

[This retracts the article DOI: 10.7150/jca.15753.].

The Epstein-Barr Virus-encoded miR-BART22 targets MAP3K5 to promote host cell proliferative and invasive abilities in nasopharyngeal carcinoma.

miR-BART22, a new discovered Epstein-Barr virus (EBV) miRNA, is abundant in Nasopharyngeal carcinoma (NPC). It has been reported that miR-BART22 promoted the tumor development by down-modulating EBV LMP2 expression to evade the host immune response. But its cell target genes have still been obscure. We have reported an inverse correlation between the BART-22 and MAP3K5 protein expression in NPC tissues and NPC cell lines. Meanwhile, MAP3K5 protein expression level was significantly decreased in primary NPC tissues compared with nasopharyngitis when MAP3K5 mRNA expression was consistent in two group tissues. According to our data and target prediction by miRnada, we assume MAP3K5 is an important target gene of NPC. MAP3K5, also named apoptosis signal-regulating kinase1 (ASK1), is an important early answer gene in P38MAPK pathway and an apoptosis-related gene. In present study, MAP3K5 was verified the target gene of miR-BART22 by luciferase assay. miRBART-22 decreased MAP3K5 protein level. Moreover, it also decreased MAP3K5 downstream gene MAP2K4 expression in P38MAPK pathway, and even their activated phosphorylation forms. Additionally, we found stable transfection of miR-BAT22 could improve tumor cells' proliferative and invasive abilities in NPC cell line 5-8F. The data highlight the role of the EBV miR-BART22 in regulating genes involving in apoptosis and some important pathways to promote cancer development. And it also raises the possibility that inhibitors of miR-BART22 can be as a therapeutic strategy for NPC and other EBV-infected tumors treatment.

Disrupting MALAT1/miR-200c sponge decreases invasion and migration in endometrioid endometrial carcinoma.

Endometrioid endometrial carcinoma (EEC) is the most common gynecologic malignancy around the world. Epithelial-to-mesenchymal transition (EMT) is a core process during EEC cell invasion. The abnormal expression of the long noncoding RNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) or miR-200 family members were shown to facilitate EMT in multiple human cancers, but the regulatory mechanism by which MALAT1 and miR-200 act remains unknown. Previous studies have shown that miR-200 family members are enriched in EEC as well as melanoma and some ovarian carcinomas. In the present study, we first showed that miR-200c levels were higher in most EEC specimens than in non-tumor tissues, while MALAT1 levels were lower. Moreover, we found that miR-200c bound directly to MALAT1 using luciferase reporter and qRT-PCR assays. MALAT1 and miR-200c are reciprocally repressed, and TGF-ß increased MALAT1 expression by inhibiting miR-200c. When the interaction between miR-200c/MALAT1 was interrupted, the invasive capacity of EEC cells was decreased and EMT markers expression were altered in vitro. A xenograft tumor model was used to show that targeting the miR-200c/MALAT1 axis inhibited EEC growth and EMT-associated protein expression in vivo. In summary, miR-200c/MALAT1 axis is a target with therapeutic potential in EEC. However, different expression model of miR-200c and MALAT1 in EEC with that in other organ carcinomas needs further mechanism researches.

A Multi-Step miRNA-mRNA Regulatory Network Construction Approach Identifies Gene Signatures Associated with Endometrioid Endometrial Carcinoma.

We aimed to identify endometrioid endometrial carcinoma (EEC)-related gene signatures using a multi-step miRNA-mRNA regulatory network construction approach. Pathway analysis showed that 61 genes were enriched on many carcinoma-related pathways. Among the 14 highest scoring gene signatures, six genes had been previously shown to be endometrial carcinoma. By qRT-PCR and next generation sequencing, we found that a gene signature (CPEB1) was significantly down-regulated in EEC tissues, which may be caused by hsa-miR-183-5p up-regulation. In addition, our literature surveys suggested that CPEB1 may play an important role in EEC pathogenesis by regulating the EMT/p53 pathway. The miRNA-mRNA network is worthy of further investigation with respect to the regulatory mechanisms of miRNAs in EEC. CPEB1 appeared to be a tumor suppressor in EEC. Our results provided valuable guidance for the functional study at the cellular level, as well as the EEC mouse models.

miR-16 induction after CDK4 knockdown is mediated by c-Myc suppression and inhibits cell growth as well as sensitizes nasopharyngeal carcinoma cells to chemotherapy.

Cyclin-dependent kinase 4 (CDK4) is a member of cyclin-dependent kinase family which regulates G1 to S cell cycle transition. CDK4 activity is increased in many tumor types. Here, we report a negative automodulatory feedback loop between CDK4 and miR-16 that regulates cell cycle progression in nasopharyngeal carcinoma (NPC). By miRNA array and real-time PCR, we identified upregulation of tumor suppressor miR-16a, which inhibited cell cycle progression and sensitized NPC cells to chemotherapy. CDK4 knockdown reduced the expression of c-Myc, the latter of which directly suppresses the miR-16 expression by directly binding to the miR-16 promoter. Moreover, we found that miR-16 upregulation could reduce CDK4 expression by repressing CCND1 and thus forms a feedback loop via the CDK4/c-Myc/miR-16/CCND1 pathway. Finally, miR-16 was negatively correlated with CDK4 expression in NPC biopsies. In summary, our results define a double-negative feedback loop involving CDK4 and miR-16 mediated by c-Myc that modulates NPC cell growth and chemotherapy sensitivity.