[Correlation of the expressions of 4-HNE and GPC5 with the progression of prostate cancer].

OBJECTIVE: To investigate the expressions of phosphatidylinositol proteoglycan 5 (GPC5) and tetrahydroxynonene (4-HNE) in the PCa tissue and their impact on tumor progression. METHODS: Using immunohistochemistry, we determined the expression rates of GPC5 and 4-HNE in 50 PCa and 50 BPH tissue samples, followed by comparative analysis of the correlation between their expressions and Gleason grading. RESULTS: The positive expression rate of GPC5 was 94.0% in the BPH tissue, remarkably higher than 86.7%, 66.7%, 75.0%, 55.6% and 33.3% in the PCa tissues of Gleason grades 1, 2, 3, 4 and 5 (P = 0.001), with a negative correlation between the positive expression rate of GPC5 and the Gleason grade of tumors (P = 0.021). In contrast, the positive expression rate of 4-HNE was 4.0% in the BPH tissue, dramatically lower than 55.6%, 66.7%, 75.0%, 77.8% and 88.9% in the PCa tissues of Gleason grades 1, 2, 3, 4 and 5 (P = 0.001), with a positive correlation between the expression rate of GPC5 and the Gleason grade of tumors (P = 0.001). After a follow-up of 10－30 months, the expression rates of GPC5 and 4-HNE in the tissues converted to castration-resistant PCa (CRPC) showed a statistically significant difference from those remaining unconverted (P = 0.001, P = 0.048). There was a negative correlation between the positive expression rate of 4-HNE and that of GPC5 in the PCa tissue (R = －0.983, P = 0.003). CONCLUSION: The low expression of GPC5 and high expression of 4-HNE are closely related to the pathological grade of PCa and its conversion to CRP, which may serve as new biological markers in assessing the malignancy and prognosis of tumors.

GHR is involved in gastric cell growth and apoptosis via PI3K/AKT signalling.

Growth hormone receptor (GHR), the cognate receptor of growth hormone (GH), is a membrane bound receptor that belongs to the class I cytokine receptor superfamily. GH binding GHR induces cell differentiation and maturation, initiates the anabolism inside the cells and promotes cell proliferation. Recently, GHR has been reported to be associated with various types of cancer. However, the underlying mechanism of GHR in gastric cancer has not been defined. Our results showed that silence of GHR inhibited the growth of SGC-7901 and MGC-803 cells, and tumour development in mouse xenograft model. Flow cytometry showed that GHR knockout significantly stimulated gastric cancer cell apoptosis and caused G1 cell cycle arrest, which was also verified by Western blot that GHR deficiency induced the protein level of cleaved-PARP, a valuable marker of apoptosis. In addition, GHR deficiency inhibited the activation of PI3K/AKT signalling pathway. On the basis of the results, that GHR regulates gastric cancer cell growth and apoptosis through controlling G1 cell cycle progression via mediating PI3K/AKT signalling pathway. These findings provide a novel understanding for the role of GHR in gastric cancer.

Cistanches alleviates sevoflurane-induced cognitive dysfunction by regulating PPAR-γ-dependent antioxidant and anti-inflammatory in rats.

This study aimed to investigate the protective effects and underlying mechanisms of cistanche on sevoflurane-induced aged cognitive dysfunction rat model. Aged (24 months) male SD rats were randomly assigned to four groups: control group, sevoflurane group, control + cistanche and sevoflurane + cistanche group. Subsequently, inflammatory cytokine levels were measured by ELISA, and the cognitive dysfunction of rats was evaluated by water maze test, open-field test and the fear conditioning test. Three days following anaesthesia, the rats were killed and hippocampus was harvested for the analysis of relative biomolecules. The oxidative stress level was indicated as nitrite and MDA concentration, along with the SOD and CAT activity. Finally, PPAR-γ antagonist was used to explore the mechanism of cistanche in vivo. The results showed that after inhaling the sevoflurane, 24- but not 3-month-old male SD rats developed obvious cognitive impairments in the behaviour test 3 days after anaesthesia. Intraperitoneal injection of cistanche at the dose of 50 mg/kg for 3 consecutive days before anaesthesia alleviated the sevoflurane-induced elevation of neuroinflammation levels and significantly attenuated the hippocampus-dependent memory impairments in 24-month-old rats. Cistanche also reduced the oxidative stress by decreasing nitrite and MDA while increasing the SOD and CAT activity. Moreover, such treatment also inhibited the activation of microglia. In addition, we demonstrated that PPAR-γ inhibition conversely alleviated cistanche-induced protective effect. Taken together, we demonstrated that cistanche can exert antioxidant, anti-inflammatory, anti-apoptosis and anti-activation of microglia effects on the development of sevoflurane-induced cognitive dysfunction by activating PPAR-γ signalling.

Promotive effect of Talin-1 protein on gastric cancer progression through PTK2-PXN-VCL-E-Cadherin-CAPN2-MAPK1 signaling axis.

OBJECTIVE: Our research group was aim to explore the molecular mechanism of Talin-1 protein affecting gastric cancer progression through PTK2-PXN-VCL-E-Cadherin-CAPN2-MAPK1 signal axis. METHODS: 12 cases of patients with gastric cancer in this hospital from 2018 to 2019 were collected. Immunohistochemistry assay and Western blotting were used to detect the expression of Talin-1, PXN, E-Cadherin, CAPN2, MAPK1 protein in gastric cancer tissue. Cell migration and invasion were measured by Transwell. RESULTS: The results showed that the expression levels of protein Talin-1, PXN and MAPK1 in gastric cancer tissues were significantly higher than that in normal tissue. The number of cell adhesion in the model group was significantly lower than that in the normal group. However, the cell adhesion number in ov-TLN1 was the highest. Transwell results showed that TLN1 could accelerate the migration and invasion abilities of gastric cancer MKN-45 cells. Moreover, Western blotting showed that protein Talin-1, PXN, E-Cadherin, CAPN2, MAPK1 in model group all increased compared with normal group. CONCLUSION: It indicated that talin-1 protein influenced the development of gastric cancer through PTK2-PXN-VCL-E-Cadherin-CAPN2-MAPK1 signal axis.

Trim14 promotes autophagy and chemotherapy resistance of gastric cancer cells by regulating AMPK/mTOR pathway.

OBJECTIVE: To study the relationship between TRIM14 expression and chemotherapy resistance of gastric cancer (GC) cells. METHODS: The expression of TRIM14 in 5-fluorouracil (5-FU)- and oxaliplation (L-OHP)-resistant GC tissues and cells were determined by qRT-PCR and western blotting. PcDNA3.1-TRIM14 and shRNA-TRIM14 vector were transfected to 5-FU-resistant GC cells (SGC7901/5-FU), and the proliferation and apoptosis of cells were measured. Animal experiments on 5-FU-resistant GC mice were performed to study the effect of TRIM14 expression on tumor size and weight, GC cell migration, and proliferation. pcDNA3.1-MK-3903 plasmid was transfected to SGC7901/5-FU cells with TRIM14 silence. The cell proliferation and apoptosis were determined. The protein expressions of Trim14, LC3, and BECLIN1 were measured by western blotting. RESULTS: TRIM14 was significantly upregulated in 5-FU- and L-OHP-resistant GC tissues and cells. The overexpression of TRIM14 promoted the proliferation and autophagy of SGC7901/5-FU cells, and inhibited the apoptosis. Moreover, in vivo experiment verified that the silence of TRIM14 reduced the tumor size and weight, and inhibited the migration and proliferation of GC cells in 5-FU-resistant GC mice. The overexpression of MK-3903 reversed the inhibiting role of TRIM14 knockout on the proliferation and autophagy of SGC7901/5-FU cells. CONCLUSION: TRIM14 promoted chemotherapy resistance of GC cells by regulating AMPK/mTOR pathway, and may be a new biomarker for treating GC.

EZH2 upregulation by ERα induces proliferation and migration of papillary thyroid carcinoma.

BACKGROUND: The incidence of papillary thyroid carcinoma (PTC) has been increasing worldwide in recent years. Therefore, novel potential therapeutic targets for PTC are urgently needed. Enhancer of zeste homolog 2 (EZH2), a methyltransferase belonging to PRC2, plays important roles in epigenetic silencing and cell cycle regulation. EZH2 overexpression has been found in several malignant tumor tissues, while its expression and function in PTC are largely unknown. METHODS: Sixty-five cases of PTC tissue confirmed by pathology and 30 cases of normal thyroid tissue adjacent to PTC tissue were collected from patients undergoing surgical treatment, between February 2003 and February 2006. We investigated the clinic pathologic significance of EZH2 expression using Realtime-PCR and IHC in 65 human PTC tissues and 30 normal thyroid tissue samples. The EZH2 expression in human PTC cell lines (K1 and W3) and the normal thyroid follicular epithelial cell line Nthy-ori 3-1 was analyzed by Western blotting and Realtime PCR. The expressions of ERα and ERß in cell lines were analyzed by Realtime PCR.The tumor cell biological behavior was evaluated by CCK8 assay, colony formation assay, transwell migration assay and xenograft tumors model. RESULTS: Higher rate of EZH2 expression was found in PTC tissues than in normal thyroid tissues, EZH2 expression is associated with lymph node metastasis and recurrent. Inhibition of EZH2 in PTC cell lines downregulates cellular proliferation and migration. PTC is a disease with high incidence of female and E2-ERα upregulates EZH2 expression. CONCLUSIONS: These results suggest a potential role of EZH2 for the PTC growth and metastasis. As a novel therapy, a pharmacological therapy targeting EZH2 has full potential in treatment of PTC.

Phosphodiesterase 4 Inhibitor Roflumilast Protects Rat Hippocampal Neurons from Sevoflurane Induced Injury via Modulation of MEK/ERK Signaling Pathway.

BACKGROUND/AIMS: Sevoflurane, a commonly used volatile anesthetic, recently has been found has neurotoxicity in the central nervous system of neonatal rodents. This study aimed to reveal whether phosphodiesterase 4 (PDE-4) inhibitor roflumilast has protective functions in sevoflurane-induced nerve damage. METHODS: Hippocampal neurons were isolated from juvenile rats, and were exposed to sevoflurane with or without roflumilast treatment. Cell viability and apoptosis were respectively assessed by CCK-8 and flow cytometry. Western blot analysis was performed to detect the protein expressions of apoptosis-related factors, and core factors in MEK/ERK and mTOR signaling pathways. RESULTS: Toxic effects of sevoflurane on hippocampal neurons were observed, as cell viability was reduced, apoptotic cell rate was increased, Bcl-2 was down-regulated, and Bax, cleaved caspase-3 and -9 were up-regulated after 1% sevoflurane exposure for 16 h. Sevoflurane exhibited a temporarily (less than 16 h) inhibitory effect on MEK/ERK pathway, but has no impact on mTOR pathway. Roflumilast promoted the release of cAMP and down-regulated the protein expression of PDE-4. Roflumilast (1 µM) alone has no impact on viability and apoptosis of hippocampal neurons. However, roflumilast increased cell viability and deceased apoptosis in sevoflurane-injured neurons. Besides, roflumilast could recover sevoflurane-induced deactivation of MEK/ERK pathway. CONCLUSION: To conclude, this study demonstrated a neuroprotective role of roflumilast in sevoflurane-induced nerve damage. Roflumilast promoted hippocampal neurons viability, and reduced apoptosis possibly via modulation of MEK/ERK signaling pathway.

Higher LRRFIP1 expression in glioblastoma multiforme is associated with better response to teniposide, a type II topoisomerase inhibitor.

Previous studies from this laboratory indicated that microRNA-21 (miR-21) contributes to chemoresistance of glioblastoma multiforme (GBM) cells to teniposide, a type II topoisomerase inhibitor. We also showed that LRRFIP1 is a target of miR-21. In this study, we found that higher baseline LRRFIP1 expression in human GBM tissue (n=60) is associated with better prognosis upon later treatment with teniposide. Experiments in cultured U373MG cells showed enhanced toxicity of teniposide against U373MG cells transfected with a vector that resulted in LRRFIP1 overexpression (vs. cells transfected with control vector). Experiments in nude mice demonstrated better response of LRRFIP1 overexpressing xenografts to teniposide. These findings indicate that high baseline LRRFIP1 expression in GBM is associated with better response to teniposide, and encourage exploring LRRFIP1 as a target for GBM treatment.

[Retracted] Yap regulates gastric cancer survival and migration via SIRT1/Mfn2/mitophagy.

Following the publication of the above article, a concerned reader drew to the Editor's attention that certain of the immunofluorescence data featured in Fig. 1H, TUNEL assay data in Fig. 2A, cytochome c leakage assay data in Fig. 2H, staining of cardiolipin images in Fig. 2H, lamellipodia­stained data in Fig. 3A, and immunofluorescence assay data in Figs. 3F and 5D were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had either already been published elsewhere prior to the submission of this paper to Oncology Reports, or were under consideration for publication at around the same time (several of which have now been retracted). In addition, overlapping sections of data were noted within the data panels in Fig. 3D and F, such that data which were intended to represent the results from differently performed experiments had apparently been derived from the same original source(s). In view of the fact that certain of these data had already apparently been published prior to the submission of this article for publication, and in view of an overall lack of confidence in the presented data, the Editor of Oncology Reports has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 39: 1671­1681, 2018; DOI: 10.3892/or.2018.6252].

[Retracted] NR4A1­induced increase in the sensitivity of a human gastric cancer line to TNFα­mediated apoptosis is associated with the inhibition of JNK/Parkin­dependent mitophagy.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the data shown in Figs. 2A and 4F were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that were submitted to their respective journals at around the same time; moreover, the same data had apparently been included in the western blots featured in Fig. 5A to show the Parkin and mito­LCIII protein bands. As it was not clear what had been the original venue for the submission of the strikingly similar data here, the Editor requested that the authors send to us all the raw data underlying the affected figures; however, the authors were not able to comply with this request at the time of asking. Given that the authors were unable to provide the supporting data as requested, the Editor of International Journal of Oncology has decided that this paper should be retracted from the Journal on account of a lack of confidence in the presented data. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 52: 367­378, 2018; DOI: 10.3892/ijo.2017.4216].

PTEN status determines therapeutic vulnerability to celastrol in cholangiocarcinoma.

BACKGROUND: A balanced protein homeostasis network helps cholangiocarcinoma (CCA) maintain their oncogenic growth, and disrupting proteostasis therapeutically will induce proteotoxic stress. Phosphatase and tensin homolog (PTEN) have been reported to be involved in proteostasis, and PTEN-associated pathways are commonly altered in CCA. Celastrol, a triterpene from plants, exhibits cytotoxic effects in various types of cancer. However, the underlying mechanisms remain unclear. PURPOSE: We investigated the therapeutic effect of celastrol in CCA and identified the molecular characteristics of tumors that were sensitive to celastrol. The target of celastrol was explored. We then evaluated the candidate combination therapeutic strategy to increase the effectiveness of celastrol in celastrol-insensitive CCA tumors. METHODS: Various CCA cells were categorized as either celastrol-sensitive or celastrol-insensitive based on their response to celastrol. The molecular characteristics of cells from different groups were determined by RNA-seq. PTEN status and its role in proteasome activity in CCA cells were investigated. The CMAP analysis, molecular docking, and functional assay were performed to explore the effect of celastrol on proteasome activities. The correlation between PTEN status and clinical outcomes, as well as proteasomal activity, were measured in CCA patients. The synergistic therapeutic effect of autophagy inhibitors on celastrol-insensitive CCA cells were measured. RESULTS: Diverse responses to celastrol were observed in CCA cells. PTEN expression varied among different CCA cells, and its status could impact cell sensitivity to celastrol: PTENhigh tumor cells were resistant to celastrol, while PTENlow cells were more sensitive. Celastrol induced proteasomal dysregulation in CCA cells by directly targeting PSMB5. Cells with low PTEN status transcriptionally promoted proteasome subunit expression in an AKT-dependent manner, making these cells more reliant on proteasomal activities to maintain proteostasis. This caused the PTENlow CCA cells sensitive to celastrol. A negative correlation was found between PTEN levels and the proteasome signature in CCA patients. Moreover, celastrol treatment could induce autophagy in PTENhigh CCA cells. Disrupting the autophagic pathway in PTENhigh CCA cells enhanced the cytotoxic effect of celastrol. CONCLUSION: PTEN status in CCA cells determines their sensitivity to celastrol, and autophagy inhibitors could enhance the anti-tumor effect in PTENhigh CCA.

The Role of YAP-JNK in the Mitophagy, Migration, and Invasion of Gastric Cancer.

OBJECTIVE: To determine the function of the YAP-JNK-mitophagy signalling pathway in gastric cancer (GC). STUDY DESIGN: An observational study. PLACE AND DURATION OF STUDY: Seventh People's Hospital of Shanghai University of TCM (Traditional Chinese Medicine), between June 2019 and June 2021. METHODOLOGY: Tissues from 30 cases of gastric cancer and corresponding adjacent tissues were collected. RT-qPCR was employed to detect the expression of YAP and JNK in GC samples. MTT, Wound healing and Transwell assays were used to detect changes in GC cell proliferation, migration, and invasion under different stimulation. LC3 immunofluorescence and mitochondrial membrane potential detection were used to analyse the occurrence of mitochondrial autophagy. RESULTS: The expression of YAP and JNK were significantly increased in GC tissues (p=0.024, 0.033). YAP knockdown inhibited GC cell proliferation, migration, and invasion. Further studies showed that YAP affects GC cell function by targeting JNK. In addition, YAP-JNK signalling was found to regulate GC cell proliferation, migration, and invasion mainly through regulating the occurrence of mitophagy. CONCLUSION: These findings revealed that YAP-JNK promotes the development of GC by targeting mitophagy. KEY WORDS: Gastric cancer, YAP, JNK, Autophagy.

miR-28-5p inhibits cholangiocarcinoma progression and predicts good prognosis of patients.

Cholangiocarcinoma (CCA) is one of the most common hepatic and biliary malignancies. The overall five-year survival rate for cholangiocarcinoma is less than 15%. miR-28-5p has been reported to participate the development of various human cancer types. But whether miR-28-5p is associated with the clinical course of CCA patients has not been clarified. Herein, we observed that miR-28-5p was reduced in CCA tissues and predicts the poor prognosis of CCA patients. Treatment with the demethylating agent 5-aza-2'-deoxycytidine (5-AZA) restored miR-28-5p expression in CCA cell lines. Furthermore, up-regulated miR-28-5p inhibited CCA cells growth and metastasis. Mechanistically, miR-28-5p suppressed CCA cells growth and metastasis via directly targeting CD44 molecular. Specific CD44 special siRNA abrogated the discrepancy of the proliferation and metastasis capacity between miR-28-5p-overexpression CCA cells and their control cells, which further confirmed that CD44 was required in miR-28-5p-inhibited CCA cell growth and metastasis.

Effect of Pretreatment of S-Ketamine On Postoperative Depression for Breast Cancer Patients.

OBJECTIVE: This study aims to investigate the effect of the pretreatment of S-ketamine on postoperative depression (POD) for breast cancer patients with mild/moderate depression. METHODS: The present randomized, double-blinded controlled trial included 303 breast cancer patients with mild/moderate depression from June 2017 to June 2018. All patients were randomly divided into three groups: (1) control group, patients treated with normal saline; (2) racemic ketamine group, patients treated with racemic ketamine; (3) S-ketamine group, patients treated with S-ketamine. Operation time, blood loss and hospital stay and complications were recorded. The Visual Analog Scale (VAS) score was recorded, and the Hamilton Rating Scale for Depression (HAMD-17) scores, serum brain-derived neurotrophic factor (BDNF) and 5-hydroxytryptamine (5-HT) were measured at three days, one week, one month and three months after surgery. RESULTS: No significant difference was found in operation time, bleeding volume and complication rate. In both groups, the VAS scores at one day and three days after surgery were significantly lower. The HAMD-17 scores were significantly lower, and the serum levels of both BDNF and 5-HT were remarkably higher at three days, one week and one month after surgery. Meanwhile, the HAMD-17 scores were remarkably lower, while the serum levels of BDNF and 5-HT were remarkably higher in the S-ketamine group. The BDNF and 5-HT levels were negatively correlated with the HAMD-17 score. CONCLUSION: S-ketamine is more effective for reducing POD for breast cancer patients.

PELP1 Suppression Inhibits Gastric Cancer Through Downregulation of c-Src-PI3K-ERK Pathway.

Background: Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1), a co-activator of estrogen receptors alpha, was confirmed to be directly associated with the oncogenic process of multiple cancers, especially hormone-dependent cancers. The purpose of our research was to explore the biological function, clinical significance, and therapeutic targeted value of PELP1 in gastric cancer (GC). Methods: The expression status of PELP1 in GC cell lines or tissues was analyzed through bioinformatics data mining. Thirty-six GC tissue chip was applied to demonstrate the results of bioinformatics data mining assayed by immunohistochemical method. The expression status of PELP1 in GC cell lines was also analyzed using western blot. Correlation analysis between PELP1 expression and clinicopathological parameter was performed. Kaplan-Meier survival analysis was applied to analyze the relationship between PELP1 expression and total survival time. Three pairs of siRNA were designed to silence the expression of PELP1 in GC. After PELP1 was silenced by siRNA or activated by saRNA, the growth, plate colony formation, migration and invasion ability of the GC cell or normal gastric epithelium cell line was tested in vitro. Cell cycle was tested by flow cytometry. Nude mice xenograft experiment was performed after PELP1 was silenced. The downstream molecular pathway regulated by PELP1 was explored. Molecular docking tool was applied to combine chlorpromazine with PELP1. The inhibitory effect of chlorpromazine in GC was assayed, then it was tested whether PELP1 was a therapeutic target of chlorpromazine in GC. Results: PELP1 expression was elevated in GC cell lines and clinical GC tissue samples. PELP1 silence by siRNA compromised the malignant traits of GC. PELP1 expression positively correlated with tumor invasion depth, lymph node metastasis, tissue grade, TNM stage, but had no correlation with patient age, sex, tumor size, and tumor numbers. Kaplan-Meier survival analysis revealed high PELP1 expression had a shorter survival period in GC patients after follow-up. Q-PCR and western blot revealed PELP1 suppression in GC decreased expression of the c-Src-PI3K-ERK pathway. It was also implied that chlorpromazine (CPZ) can inhibit the malignant traits of GC and downregulate the expression of PELP1. Conclusions: In a word, PELP1 is an oncogene in gastric cancer and c-Src-PI3K-ERK pathway activation may be responsible for its tumorigenesis, PELP1 may be a potential therapeutic target of chlorpromazine in GC.

Yap regulates gastric cancer survival and migration via SIRT1/Mfn2/mitophagy.

Gastric cancer is the fifth most common cancer worldwide and Hippo-Yap is the novel signaling pathway which plays an important role in gastric cancer tumor development and progression. However, little insight is available to date regarding the specific role of Yes-associated protein (Yap) in gastric cancer. In the present study, we identified the mechanism through which Yap sustains gastric cancer viability and migration. Yap was greatly upregulated in gastric cancer cells and its expression promoted cellular migration and survival. Functional studies found that knockdown of Yap reduced the mitophagy activity, which subsequently caused mitochondrial apoptosis and cellular oxidative stress. The latter impaired adhesive protein expression, alleviated F-actin expression, blunted lamellipodium formation, leading to inhibition of cancer cell motility. Mechanistically, Yap preserved Sirtuin 1 (SIRT1) activity which manipulated mitofusin 2 (Mfn2) expression and subsequent mitophagy. Loss of Yap reduced SIRT1 expression and inhibited Mfn2-mediated mitophagy. Collectively, our results identified Hippo-Yap as a tumor promoter in gastric cancer that was mediated via activation of the SIRT1/Mfn2/mitophagy axis, with potential applications to gastric cancer therapy involving cancer survival and migration.

NR4A1-induced increase in the sensitivity of a human gastric cancer line to TNFα-mediated apoptosis is associated with the inhibition of JNK/Parkin-dependent mitophagy.

Tumor necrosis factor α (TNFα)-based immunotherapy is the vital host defense system against the progression of gastric cancer (GC) as a pro-inflammatory and pro-apoptotic cytokine. However, resistance limits its therapeutic efficiency. Therefore, an increasing number of studies are focusing on the development of drugs or methods with which to enhance the treatment efficacy of TNFα. Nuclear receptor subfamily 4 group A member 1 (NR4A1) has been shown to exert antitumor effects through several mechanisms, such as by inhibiting proliferation, as well as pro-apoptotic and potent pro-oxidant effects. In this study, we examined the effects and mechanisms of action of NR4A1 on the apoptosis of GC cells treated with TNFα, with particular focus on mitochondrial homeostasis. We found that TNFα treatment decreased NR4A1 expression. Moreover, the overexpression of NR4A1 in the presence of TNFα further increased GC cell apoptosis. Mechanistically, the overexpression of NR4A1 augmented caspase-9-dependent mitochondrial apoptosis, as evidenced by reduced mitochondrial membrane potential, reactive oxygen species (ROS) overproduction, mitochondrial permeability transition pore (mPTP) opening and the leakage of cytochrome c (Cyt-c) leakage. Moreover, NR4A1 overexpression also evoked mitochondrial energy disorder via the suppression of mitochondrial respiratory complex expression. Furthermore, we found that TNFα treatment activated Parkin-dependent mitophagy. Excessive Parkin-dependent mitophagy blocked mitochondrial apoptosis, undermining the toxic effects of TNFα on cells. However, NR4A1 overexpression suppressed Parkin-dependent mitophagy via the inhibition of c-Jun N-terminal kinase (JNK). Re-activation of the JNK/Parkin pathway abrogated the inhibitory effects of NR4A1 on mitophagy, eventually limiting cell apoptosis. Collectively, this study confirmed that NR4A1 sensitizes GC cells to TNFα-induced apoptosis through the inhibition of JNK/Parkin-dependent mitophagy.

Co-culture of hepatoma cells with hepatocytic precursor (stem-like) cells inhibits tumor cell growth and invasion by downregulating Akt/NF-κB expression.

Hepatocytic stem cells (HSCs) have inhibitory effects on hepatocarcinoma cells. The present study investigated the effects of HSC activity in hepatocarcinoma cells in vitro. A Transwell co-culture system of hepatocytic precursor (stem-like) WB-F344 cells and hepatoma CBRH-7919 cells was used to assess HSC activity in metastasized hepatoma cells in vitro. Nude mouse xenografts were used to assess HSC activity in vivo. Co-culture of hepatoma CBRH-7919 cells with WB-F344 cells suppressed the growth and colony formation, tumor cell migration and invasion capacity of CBRH-7919 cells. The nude mouse xenograft assay demonstrated that the xenograft size of CBRH-7919 cells following co-culture with WB-F344 cells was significantly smaller compared with that of control cells. Furthermore, the expression levels of the epithelial markers E-cadherin and ß-catenin were downregulated, while the mesenchymal markers α-SMA and vimentin were upregulated. Co-culture of CBRH-7919 cells with WB-F344 cells downregulated NF-κB and phospho-Akt expression. In conclusion, hepatocytic precursor (stem-like) WB-F344 cells inhibited the growth, colony formation and invasion capacity of metastasized hepatoma CBRH-7919 cells in vitro and in vivo by downregulating Akt/NF-κB signaling.

Renal carcinoid tumor with liver metastasis followed up postoperatively for 9 years.

BACKGROUND: We describe a case of renal carcinoid tumor with liver metastasis followed up postoperatively for 9 years. CASE PRESENTATION: A 33-year-old man presented with left flank dull ache. On the abdominal computed tomography, a solid renal mass in the upper portion of the left kidney was detected. The patient had no other abnormal findings, such as suspected distant metastasis or lymph node metastasis. Radical nephrectomy was performed on 14/9/2005. Histological examination and immunohistochemical staining confirm primary renal carcinoid tumor. 9 years after radical nephrectomy, computed tomography of the abdomen demonstrated a 2 cm × 1.8 cm cyst mass in the right liver. Similar pathologic characteristics were found between the renal carcinoid tumor and liver tumor. CONCLUSIONS: We present a primary renal carcinoid tumor with liver metastasis 9 years after radical nephrectomy. With literature review, renal carcinoid tumors exhibit heterogenous behavior.

Alveolar adenoma combined with multifocal cysts: case report and literature review.

Alveolar adenoma is an extremely rare and benign pulmonary neoplasm; it is always asymptomatic and is usually detected incidentally on routine chest X-radiography. Typically on imaging examinations, alveolar adenoma exhibits as a peripheral, solitary, cystic nodule in the lung, which may easily imitate other lung lesions, consequently leading to difficulties in the differential diagnosis of this condition. Surgical resection is the primary treatment option. The diagnosis of alveolar adenoma is mainly based on postoperative histopathology, with features of proliferative type 2 alveolar epithelial cells and septal mesenchyme. The present case was a 60-year-old woman with alveolar adenoma, combined with systemic mutifocal cystic lesions. She underwent surgery following the obvious enlargement of this mass and a cystic nodule 7 cm in maximum diameter was resected. Postoperative histopathology confirmed a diagnosis of alveolar adenoma; her prognosis was favourable. In addition to reporting a rare case of alveolar adenoma coexisting with multifocal cysts, the English-language literature was reviewed for similar cases of alveolar adenoma.