Analytical Cellular Pathology最新文献

Progesterone receptor (PR) is a member of the nuclear/steroid hormone receptor family of ligand-dependent transcription factors. It plays an important role in reproduction and mammary gland development and has various tissue-specific effects in nonreproductive organs. In diagnostic pathology, positive PR immunostaining is used to support a diagnosis of breast or gynecologic origin in a tumor. In this study, the expression of PR was analyzed by immunohistochemistry in 18,176 (interpretable: 16,445) samples from 147 different tumor types and subtypes in a tissue microarray format. PR immunostaining was detected in 57.4% of breast tumors, 28.6% of other gynecological tumors, and 1.8% of nongynecological and nonmammary tumors. Among the group of nongynecological and nonmammary tumors, particularly high rates of PR positivity were seen in neuroendocrine tumors (54.3%) and neuroendocrine carcinomas (35.7%) of the pancreas. A comparison with clinico-pathological parameters showed that reduced PR immunostaining was significantly associated with adverse histopathological and clinical features in breast carcinoma, endometrioid endometrial carcinoma, and pancreatic neuroendocrine tumors. In summary, our analysis of 147 different tumor types for PR immunostaining provides a ranking list of tumor entities according to their prevalence of PR positivity, helps to better understand the diagnostic utility of PR, and highlights the distinct PR positivity among neuroendocrine neoplasms of pancreatic origin.

Objective: Glioblastoma is one of the most common malignant tumors in the brain, and these glioblastoma patients have very poor prognosis. Ferroptosis is involved in the progression of various tumors, including the glioblastoma. This study aims to determine the involvement of microRNA (miR)-147a in regulating ferroptosis of glioblastoma in vitro.

Methods: Human glioblastoma cell lines were transfected with the inhibitor, mimic and matched negative controls of miR-147a in the presence or absence of ferroptotic inducers. To knock down the endogenous solute carrier family 40 member 1 (SLC40A1), cells were transfected with the small interfering RNA against SLC40A1. In addition, cells with or without the miR-147a mimic treatment were also incubated with temozolomide (TMZ) to investigate whether miR-147a overexpression could sensitize human glioblastoma cells to TMZ chemotherapy in vitro.

Results: We found that miR-147a level was decreased in human glioblastoma tissues and cell lines and that the miR-147a mimic significantly suppressed the growth of glioblastoma cells in vitro. In addition, miR-147a expression was elevated in human glioblastoma cells upon erastin or RSL3 stimulation. Treatment with the miR-147a mimic significantly induced ferroptosis of glioblastoma cells, and the ferroptotic inhibitors could block the miR-147a mimic-mediated tumor suppression in vitro. Conversely, the miR-147a inhibitor prevented erastin- or RSL3-induced ferroptosis and increased the viability of glioblastoma cells in vitro. Mechanistically, we determined that miR-147a directly bound to the 3'-untranslated region of SLC40A1 and inhibited SLC40A1-mediated iron export, thereby facilitating iron overload, lipid peroxidation, and ferroptosis. Furthermore, miR-147a mimic-treated human glioblastoma cells exhibited higher sensitivity to TMZ chemotherapy than those treated with the mimic control in vitro.

Conclusion: We for the first time determine that miR-147a targets SLC40A1 to induce ferroptosis in human glioblastoma in vitro.

Background: Renal cell carcinoma (RCC) is a frequent disease with limited curative methods. This study is aimed at investigating the role and mechanism of Radix Actinidia chinensis (RAC) on RCC.

Methods: The ingredients, target, and crucial pathways of RAC in RCC therapy were analyzed by network pharmacology. Then, an RCC animal model was established by subcutaneously injecting A498 cell suspension to BALB/c nude mice. After 1 week, the mice in the RAC-L/M/H groups were administered with RAC at 5, 10, and 20 mg/kg/d, respectively. The histopathology of the tumor was evaluated. The contents of tumor inflammatory cytokines and serum oxidative stress factors were detected by ELISA. The apoptosis of tumor tissues was assessed by TUNEL staining. The expressions of apoptosis-, proliferate-, autophagy-, and MAPK-related proteins were measured.

Results: There were 13 active ingredients, and 20 RCC-relevant targets were selected from RAC; KEGG pathway indicated that these targets were enriched in the PI3K/AKT/mTOR and MAPK pathway. In in vivo experiments, RAC not only obviously damaged tumor cells and decreased the release of inflammatory cytokines and oxidative stress factors but also enhanced the apoptosis of the tumor cell in RCC mice. Besides, the expressions of apoptosis-, proliferate-, autophagy-, PI3K/AKT/mTOR path-, and MAPK path-related proteins were all affected by RAC.

Conclusion: RAC attenuated RCC by regulating inflammation response, oxidative stress, apoptosis, proliferation, and autophagy, and its effects were partly linked to the PI3K/AKT/mTOR and MAPK pathway, which indicated that RAC may be a candidate drug for RCC.

Esophageal carcinoma (EC) is the most prevalent malignant tumor that occurs frequently worldwide. The early diagnostic biomarkers are crucial for EC treatment. miRNA can regulate EC progression, with diagnostic and prognostic value. Herein, differentially expressed miRNAs and mRNAs (DEmRNAs) in EC were predicted based on TCGA database. The target mRNAs of miRNA were predicted through databases, which were then intersected with DEmRNAs. Next, the correlation between miRNA and candidate mRNAs was analyzed. qRT-PCR was introduced to analyze expression of miR-145-3p and CXCL5 mRNA in EC cell lines, and western blot was performed to assess protein expression of CXCL5. Cell proliferation, migration, invasion, and apoptosis in EC were examined through CCK-8, wound healing, Transwell invasion, and flow cytometry assays. Moreover, targeting relationship between miR-145-3p and CXCL5 was verified through luciferase reporter gene analysis. The experimental results revealed a decreased miR-145-3p expression and an increased CXCL5 expression in EC. Enforced expression of miR-145-3p hindered proliferation, migration, invasion, and stimulated apoptosis of EC cells by repressing CXCL5. This study manifested that miR-145-3p may be a tumor suppressor in EC, and miR-145-3p/CXCL5 axis restrained the malignant progression of EC. These results supply an underlying target for prognosis and treatment of EC patients.

X-box binding protein 1 (XBP1) is a transcription factor that recognizes the CRE-like element in enhancers of human T-cell leukemia virus and MHC class II gene and induces their transcription. This study was performed to characterize the function of XBP1, which was identified to be a differentially expressed gene via GEO database, in chronic rhinosinusitis (CRS) without nasal polyps (CRSsNP). XBP1 expression was significantly elevated in both CRSsNP patients and mice who were accompanied with mucosal thickening, goblet cell hyperplasia and chemosis, glandular hyperplasia, and dense infiltration of inflammatory cells. Silencing of XBP1 suppressed the development of CRSsNP in mice. Mechanistically, knockdown of XBP1 downregulated the expression of hypoxia-inducible factor 1-alpha (HIF-1a), and overexpression of XBP1 led to the opposite result. Silencing of HIF-1a inhibited β-catenin expression and impaired the Wnt/β-catenin pathway. Further overexpression of HIF-1a in XBP1-silenced CRSsNP mice exacerbated pathological changes in mouse nasal mucosal tissues, promoted inflammation, and activated the Wnt/β-catenin pathway. Taken together, overexpression of XBP1 may be associated with increased expression of HIF-1a and possibly contribute to the Wnt/β-catenin pathway activation and the development of CRSsNP.

Medulloblastoma is one of the most common malignant tumors of the central nervous system in children. Although KIF2B was reported as an oncogene in several malignant tumor types, its role in medulloblastoma has not been studied so far. The PCR results of our study showed that KIF26B is highly expressed in medulloblastoma, and its high expression is associated with a high clinical stage. Knockdown the expression of KIF26B could significantly impair the proliferation and migration of medulloblastoma cells. KIF26B promotes the malignant progression of medulloblastoma by affecting the expression of phosphorylation of key proteins in the PI3K/AKT signaling pathway. With the help of 740 Y-P, activating the pi3k signaling pathway can partially rescue the phenotype. Therefore, our experimental results suggest that KIF26B is a potential target for medulloblastoma.

This study used a metabolomic approach to reveal changes in the levels of metabolic biomarkers and related metabolic pathways before and after Zhuang Yao Shuang Lu Tong Nao granule (YHT) treatment in rats with cerebral ischemia. The neurological deficit scores were significantly higher in the MCAO_R group than in the NC group, indicating that the mice had significantly impaired motor functions. The YHT group had significantly lower scores than the MCAO_R group, suggesting that YHT significantly improved motor function in rats. TTC staining of the brain tissue revealed that YHT significantly reduced the area of cerebral infarction in the treated rats. The MCAO_R group was better separated from the NC rent, sham, and YHT groups via metabolomic PCA. Moreover, there were significant differences in the differential metabolites between the MACO_R and YHT groups. Eighteen common differential metabolites were detected between the MACO_R and NC groups, MACO_R and sham groups, and MACO_R and YHT groups, indicating that YHT significantly increased the levels of various metabolites in the serum of cerebral ischemic stroke (CIS) rats. Moreover, a total of 23 metabolic pathways were obtained. We identified 11 metabolic pathways with the most significant effects in the bubble plots. In conclusion, from a systems biology perspective, this metabolomics-based study showed that YHT could be used to treat ischemic stroke by modulating changes in endogenous metabolites.

Background: To investigate the relationship between primary ovarian insufficiency and autophagy, we detected and got the expression profile of human granulosa cell line SVOG, which was with or without LPS induced. The expression profile was analyzed with the focus on the autophagy genes, among which hub genes were identified.

Results: Totally, 6 genes were selected as candidate hub genes which might correlate with the process of primary ovarian insufficiency. The expression of hub genes was then validated by quantitative real-time PCR and two of them had significant expression change. Bioinformatics analysis was performed to observe the features of hub genes, including hub gene-RBP/TF/miRNA/drug network construction, functional analysis, and protein-protein interaction network. Pearson's correlation analysis was also performed to identify the correlation between hub genes and autophagy genes, among which there were four autophagy genes significantly correlated with hub genes, including ATG4B, ATG3, ATG13, and ULK1.

Conclusion: The results indicated that autophagy might play an essential role in the process and underlying molecular mechanism of primary ovarian insufficiency, which was revealed for the first time and may help to provide a molecular foundation for the development of diagnostic and therapeutic approaches for primary ovarian insufficiency.

Endometriosis (EMs) is one of the most common gynecological diseases, lacking effective treatment. EMs are currently being treated with small molecule targeted therapy, which has resulted in a significant reduction in patient suffering. Our previous studies have shown that sunitinib plays an obvious role in migration. Consequently, the purpose of this study is to explore the molecular mechanism by which sunitinib suppressed the ectopic endometrial migration. The ectopic endometrial cells from patients were divided into two groups: the control group and the sunitinib group. Co-IP and protein spectrum assay were employed to filtrate differential proteins between two groups, and then, our study discovered a signaling pathway, p-VEGFR-PI3K-AKT-YBX1-Snail, in the cell of EMs. To confirm this signaling pathway, VEGF165 was added to the sunitinib group to upregulate the expression of VEGFR. Next, the expression of p-VEGFR, PI3K, AKT, YBX1, and snail was measured in the control group and sunitinib group (compared with the control group: p-VEGFR, PI3K, AKT, YBX1, and snail, ∗∗∗∗P < 0.0001) and the VEGFR+sunitinib group (compared with the sunitinib group: p-VEGFR, PI3K, AKT, and snail, ∗∗∗∗P < 0.0001; YBX1, ∗∗∗P < 0.001); finally, the outcome was as expected. In addition to in vitro experiments, we also conducted in vivo experiments in mice. In the EMs mouse model, we found sunitinib reduced the number of heterotopic foci (t = 11.16, ∗∗∗∗P < 0.0001) and inhibited the expression of p-VEGFR, YBX1, and snail by immunofluorescence. To sum up, sunitinib exactly reduced the migration of ectopic endometrial cells with the involvement of the p-VEGFR-PI3K-AKT-YBX1-Snail signaling pathway in both in vitro and in vivo experiments. This study suggests that sunitinib presents a potential targeted drug for EMs therapy.

Acute kidney injury (AKI) is an important public health concern and characterized as tubular death involved in apoptosis and necrosis. Autophagy is rapidly induced in tubules and associates with renal tubular cells homeostasis to have a complex link with tubular death in AKI. Numb is a multifunctional protein and exerts protective role in tubular death in AKI induced by Cisplatin. However, the effect of Numb on tubular autophagy remains to be investigated. In the present study, the protein expression of LC3 and Beclin-1 related to autophagy was analyzed in Cisplatin-induced AKI mice with knocking down Numb. In model of tubular injury induced by Cisplatin in vitro, downregulation of Numb in NRK-52E cells also inhibited the activation of autophagy accompanied with the decreased protein level of p53. Overexpression of Numb in NRK-52E cells activated autophagy with increased LC3 and Beclin-1 expression accompanied with increased protein level of p53. Moreover, autophagy activation following Numb overexpression was suppressed by p53 inhibitor pifithrin-α. These data indicate that Numb promotes p53-mediated activation of tubular autophagy in AKI induced by Cisplatin and therefore may provide important targets for the treatment of AKI.