Camellia oleifera CoSWEET10 Is Crucial for Seed Development and Drought Resistance by Mediating Sugar Transport in Transgenic Arabidopsis.

Sugar transport from the source leaf to the sink organ is critical for seed development and crop yield, as well as for responding to abiotic stress. SWEETs (sugar will eventually be exported transporters) mediate sugar efflux into the reproductive sink and are therefore considered key candidate proteins for sugar unloading during seed development. However, the specific mechanism underlying the sugar unloading to seeds in Camellia oleifera remains elusive. Here, we identified a SWEET gene named CoSWEET10, which belongs to Clade III and has high expression levels in the seeds of C. oleifera. CoSWEET10 is a plasma membrane-localized protein. The complementation assay of CoSWEET10 in SUSY7/ura3 and EBY.VW4000 yeast strains showed that CoSWEET10 has the ability to transport sucrose, glucose, and fructose. Through the C. oleifera seeds in vitro culture, we found that the expression of CoSWEET10 can be induced by hexose and sucrose, and especially glucose. By generating the restoration lines of CoSWEET10 in Arabidopsis atsweet10, we found that CoSWEET10 restored the seed defect phenotype of the mutant by regulating soluble sugar accumulation and increased plant drought tolerance. Collectively, our study demonstrates that CoSWEET10 plays a dual role in promoting seed development and enhancing plant drought resistance as a sucrose and hexose transporter.

Hsa-miR-301a-3p inhibited the killing effect of natural killer cells on non-small cell lung cancer cells by regulating RUNX3.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most commonly diagnosed solid tumor. Natural killer (NK) cell-based immunotherapy is a promising anti-tumor strategy in various cancers including NSCLC. OBJECTIVE: We aimed to investigate the specific mechanisms that regulate the killing effect of NK cells to NSCLC cells. METHODS: Reverse transcription-quantitative PCR (RT-qPCR) assay was applied to measure the levels of hsa-microRNA (miR)-301a-3p and Runt-related transcription factor 3 (RUNX3). Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of IFN-γ and TNF-α. Lactate dehydrogenase assay was applied to detect the killing effect of NK cells. Dualluciferase reporter assay and RNA immunoprecipitation (RIP) assay were carried out to confirm the regulatory relationship between hsa-miR-301a-3p and RUNX3. RESULTS: A low expression of hsa-miR-301a-3p was observed in NK cells stimulated by IL-2. The levels of IFN-γ and TNF-α were increased in NK cells of the IL-2 group. Overexpression of hsa-miR-301a-3p reduced the levels of IFN-γ and TNF-α as well as the killing effect of NK cells. Furthermore, RUNX3 was identified to be a target of hsamiR-301a-3p. hsa-miR-301a-3p suppressed the cytotoxicity of NK cells to NSCLC cells by inhibiting the expression of RUNX3. We found hsa-miR-301a-3p promoted tumor growth by suppressing the killing effect of NK cells against NSCLC cells in vivo. CONCLUSIONS: Hsa-miR-301a-3p suppressed the killing effect of NK cells on NSCLC cells by targeting RUNX3, which may provide promising strategies for NK cell-based antitumor therapies.

Mitochondria-associated gene expression perturbation predicts clinical outcomes and shows potential for targeted therapy in neuroblastoma.

Background: Mitochondria have long been considered a potential target in cancer therapy because malignant cells are known for their altered energy production. However, there is a lack of comprehensive research on the involvement of mitochondria-associated proteins (MAPs) in neuroblastoma (NB), and their potential as therapeutic targets is yet to be fully explored. Methods: MAP genes were defined based on the protein-coding genes with mitochondrial localization. The mRNA expression patterns and dynamics of MAP genes associated with NB were investigated by integrating publicly available transcriptional profiles at the cellular and tissue levels. Multivariate Cox regression analysis was conducted to reveal the association of MAP genes with the overall survival (OS) and clinical subgroups of NB patients. The single-cell RNA-seq dataset and gene dependency screening datasets were analyzed to reveal the therapeutic potential of targeting MAP genes. Results: We compiled a total of 1,712 MAP genes. We found the global and cell type-specific mRNA expression changes of the MAP genes associated with NB status and survival. Our analyses revealed a group of MAP gene signatures independent of MYCN-amplification status associated with NB outcome. We provided computational evidence with selected MAP genes showing good performance in predicting long-term prognosis. By analyzing gene dependency of the MAP genes in NB cell lines and ex vivo human primary T cells, we demonstrated the therapeutic potential of targeting several MAP genes in NB tumors. Conclusions: Collectively, our study provides evidence for the MAP genes as extended candidates in NB tumor stratification and staging, prognostic prediction, and targeted drug development.

Mitochondrial creatine kinase 1 regulates the cell cycle in non-small cell lung cancer via activation of cyclin-dependent kinase 4.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the main type of the most common malignant tumor in the world. Previous studies have shown that the expression level of mitochondrial creatine kinase 1 (CKMT1) is abnormal in NSCLC, but the mechanism of its effect remains unclear. Therefore, in this study, we intend to clarify the potential mechanism of CKMT1 in NSCLC and provide the theoretical basis for the clinical application of CKMT1. METHODS: The function of CKMT1 in NSCLC was identified by analyzing the GEO dataset and evaluating using in vitro and in vivo models. Protein mass spectrometry was used to find proteins interacting with CKMT1, and Co-immunoprecipitation (Co-IP) and GST-pull down experiments were used to verify the interaction between proteins. The immunofluorescence (IF) assay was used to explore the functional position of CKMT1 in cells. The effect of CKMT1 expression level on the efficacy of paclitaxel (TAX) in the treatment of NSCLC was analyzed by a combined TAX experiment in vivo and in vitro. RESULTS: CKMT1 expression was increased in NSCLC and CKMT1 promoted the proliferation of NSCLC cells in vitro and in vivo. CKMT1 knockdown resulted in a significantly increased G0/G1 fraction and decreased S phase cell fraction, indicating G1 phase arrest. Mechanically, the cyclin-dependent kinase 4 (CDK4) was identified to interact with CKMT1, and the crucial binding areas were focused on the DH domain of CKMT1 and the N- and C-terminal of CDK4. A fraction of the CDK4 proteins colocalize and interact with the CKMT1 at mitochondria, the level of phosphorylated CDK4 was regulated by CKMT1. Hence, the decrease in CKMT1 expression level could increase the antitumor effect of G2/M cell cycle antagonist-TAX in NSCLC in vitro and in vivo. CONCLUSIONS: CKMT1 could interact with CDK4 in mitochondria and regulate the phosphorylated level of CDK4, thus contributing to the proliferation and cell cycle transition of NSCLC cells. And CKMT1 could be a potential target to improve the sensitivity of chemotherapy based on TAX.

Leptospira infection complicated by demyelinating disease: A case report.

Leptospirosis is a zoonotic disease, found worldwide, that is caused by bacteria of the genus Leptospira. People can be infected with Leptospira if they come in direct contact with the urine of an infected animal. Leptospirosis may be associated with demyelinating lesions of the central nervous system. This case report describes a 66-year-old female patient who presented with fever and generalized aches and progressed to unconsciousness within a few hours of admission. Laboratory tests showed Leptospira infection, and brain magnetic resonance imaging revealed acute demyelinating lesions. The patient responded well to penicillin and intravenous methylprednisolone therapy. Leptospirosis presenting with acute disseminated encephalomyelitis is rare. In this patient, an interdisciplinary collaboration involving the neurologist, radiologist, and pathologist was crucial for diagnosis and management. Further studies are warranted to investigate whether there is a correlation between demyelinating lesions and leptospiral infection.

PCDH1 promotes progression of pancreatic ductal adenocarcinoma via activation of NF-κB signalling by interacting with KPNB1.

Uncontrolled growth, distant metastasis and chemoresistance are critical characteristics of pancreatic ductal adenocarcinoma (PDAC), and they result in high mortality; however, the mechanisms triggering these effects have not been fully investigated. In this study, we analysed a dataset in the Cancer Genome Atlas (TCGA) and identified PCDH1, a rarely studied transmembrane protein, as a novel prognostic marker in PDAC patients. We demonstrated that PCDH1 expression was upregulated in PDAC tissues, and its expression levels were associated with the depth of tumour invasion and lymph node metastasis. Patients with high PCDH1 levels showed poor overall survival (OS). We also investigated the biological significance of PCDH1 in PDAC cell growth, metastasis, and side population (SP) phenotype acquisition and explored the internal molecular mechanisms of PCDH1 action. Our results demonstrated that PCDH1 enhanced p65 nuclear localization by interacting with KPNB1, a well-characterized nuclear transporter, thereby activating the NF-κB signalling pathway and increasing its functional effects during PDAC progression. Hence, our results indicate that PCDH1 can be used as a negative prognostic marker and may be a potential therapeutic target for PDAC patients.

LncRNA SNHG1 promotes renal cell carcinoma progression through regulation of HMGA2 via sponging miR-103a.

BACKGROUND: Long noncoding RNAs (LncRNAs) plays a vital role in tumorigenesis and development. The molecular mechanism of SNHG1 in renal cell carcinoma (RCC) has not been illustrated. The aim of this research was to explore the expression and function of LncRNA SNHG1 in RCC. MATERIAL AND METHODS: The expression of SNHG1 in clinical tissues and RCC cell lines was detected. Luciferase reporter assay was performed to verify the correlation between SNHG1, miR-103a, and HMGA2. CCK-8 assay was performed to examine cell viability. Cell apoptosis was analyzed using flow cytometry. Cell invasion capacity was determined by Transwell assays. The protein level of HMGA2 was analyzed by Western blotting. RESULTS: The expression of SNHG1 markedly increased in RCC tissues and cell lines. Subsequent studies identified SNHG1 as a miRNA sponge for miR-103a. In addition, SNHG1 knockdown and miR-103a overexpression significantly inhibited progression of RCC. miR-103a also regulated HMGA2 levels. CONCLUSION: Our findings showed that SNHG1 was upregulated in RCC cells and tissues. SNHG1 promoted the malignant characteristics of RCC cells. Its regulatory effect may be regulation of HMGA2 by sponging miR-103a. Therefore, Our study facilitates the understanding of SNHG1 function in RCC.

Long Noncoding RNA FOXD2-AS1 Promotes Pancreas Adenocarcinoma Cell Invasion and Migration by Sponging miR-30a-3p to Upregulate COX-2.

INTRODUCTION: FOXD2-AS1 is known to promote the development of several cancers. However, its role in pancreatic adenocarcinoma (PAAD) is unclear. METHODS: Expression of FOXD2-AS1 and miR-30a-3p in PAAD patients was analyzed with RT-qPCR. A follow-up study was performed to analyze the prognostic value of FOXD2-AS1 for PAAD. Overexpression assays were performed to analyze the crosstalk between FOXD2-AS1 and miR-30a-3p. Cell invasion and migration were analyzed by transwell assays. RESULTS: Analysis of the TCGA dataset revealed that FOXD2-AS1 was upregulated in PAAD tissues compared to the non-cancer tissues (1.89 vs. 0.2 TPM), indicating potential involvement of FOXD2-AS1 in PAAD. Our own data also showed FOXD2-AS1 was overexpressed in PAAD. Moreover, high FOXD2-AS1 levels predicted poor survival. It is predicted that miR-30a-3p can bind FOXD2-AS1, while their overexpression did not affect each other's expression. Correlation analysis revealed a significant correlation between FOXD2-AS1 and COX-2. In addition, FOXD2-AS1 overexpression increased COX-2 level, while miR-30a-3p played an opposite role. FOXD2-AS1 and COX-2 overexpression increased PAAD cell invasion and migration. MiR-30a-3p played an opposite role and inhibited the effects of FOXD2-AS1 and COX-2 overexpression. CONCLUSION: FOXD2-AS1 may promote PAAD cell invasion and migration by sponging miR-30a-3p to upregulate COX-2.

Diagnosis and treatment of traumatic duodenal rupture in children.

BACKGROUND: The purpose of this study was to investigate the diagnosis and treatment experience of traumatic duodenal ruptures in children. METHODS: Clinical data were collected from four children suffering from a traumatic duodenal rupture who were admitted to and treated by our hospital from January 2012 to December 2020. The early diagnosis and treatment, surgical plan, postoperative management, complications, and prognosis of each child were analyzed. The key points and difficulties of the diagnosis and treatment for this type of injury are summarized. RESULTS: One child had an extreme infection caused by drug-resistant bacteria, which resulted in severe complications, including wound infection, dehiscence, and an intestinal fistula. One child developed an anastomotic stenosis after the duodenostomy, which improved following an endoscopic balloon dilatation. The other two children had no relevant complications after their operations. All four patients were cured and discharged from hospital. The average hospital stay was 48.25 ± 26.89 days. The follow-up period was 0.5 to 1 year. No other complications occurred, and all children had a positive prognosis. CONCLUSIONS: The early identification of a duodenal rupture is essential, and surgical exploration should be carried out proactively. The principles of damage-control surgery should be followed as much as possible during the operation. Multidisciplinary cooperation and management are both important to reduce the occurrence of postoperative complications and improve cure rates.

Application of Embedding Hepaticojejunostomy in Children with Pancreaticobiliary Maljunction Without Biliary Dilatation.

Background: To investigate the effect of embedded hepaticojejunostomy in children with pancreaticobiliary maljunction (PBM) without biliary dilatation. Materials and Methods: The clinical data of 10 patients with nondilated PBM from February 2017 to July 2020 were retrospectively analyzed. Perioperative liver function indexes were compared. Results: All patients were diagnosed by magnetic resonance cholangiopancreatography (MRCP) combined with intraoperative cholangiography. There were 5 cases of Komi type I and 5 cases of type II; the diameter of the common bile duct was 4-9 mm (median: 6 mm); and the length of the common channel was 5-15 mm (median: 9.25 mm). The procedure for one patient with common duct stones was converted to open surgery. Laparoscopic cholecystectomy, common bile duct resection, and embedded hepaticojejunostomy were successfully performed in all 10 cases. The average operation time was 225 ± 96.64 min, and the intraoperative blood loss was 2-5 mL. The mean time to oral intake was 3.5 ± 1.65 days (range: 2-5 days), and the mean hospitalization duration was 6.2 ± 2.44 days (range: 5-8 days). The differences in liver function indexes in the perioperative period were statistically significant (P < .05). The patients were followed-up for 13 to 54 months (median: 40 months). All patients grew well and there was no bile duct dilatation, calculus, or cirrhosis on B-ultrasound examinations. Conclusions: The clinical manifestations of nondilated PBM are often concealed, and preoperative MRCP was important for obtaining a diagnosis. Laparoscopic cholecystectomy, common bile duct resection, and embedded hepaticojejunostomy are feasible for treating nondilated PBM.

RNA-binding protein RBM6 acts as a tumor suppressor gene to inhibit the progression of hepatocellular carcinoma.

PURPOSE: To investigate whether RBM6 can serve as a suppressor gene in hepatocellular carcinoma (HCC) and affect its progression. METHODS: QPCR and Western blot were carried out to measure RBM6 expression in tissue samples collected from HCC patients with different tumor sizes or in different stages. The relationship between overall survival (OS) and RBM6 expression in patients with HCC was analyzed using Kaplan-Meier survival method. Meanwhile, the effects of different factors on HCC progression were evaluated through Cox regression analysis. After over-expression of RBM6 in HepG2 and HB611 cells, the cell viability, cell migration and invasion abilities and apoptosis rate were assessed by cell counting kit-8 (CCK-8), transwell assay, and flow cytometry analysis, respectively. RESULTS: RBM6 expression, markedly down-regulated in HCC tissues, showed a great relevance to tumor size, TNM stage, and histological grade, and the survival rate of patients in high RBM6 expression group was higher than those in low RBM6 expression group. Besides, Cox regression analysis revealed that RBM6 expression, tumor size, TNM stage and histological grade were four independent factors affecting the OS of HCC patients. Moreover, in vitro cell experiments demonstrated that overexpression of RBM6 significantly attenuated the cell viability as well as the invasive ability while enhanced cell apoptosis. CONCLUSIONS: The low expression of RBM6 contributes to the improvement of the survival of patients with HCC. Therefore, RBM6 can serve as a tumor-suppressing gene to repress cell proliferation, migration and invasion and promote cell apoptosis, thereby affecting the progression of HCC.

Ubiquitin-specific peptidase 53 inhibits the occurrence and development of clear cell renal cell carcinoma through NF-κB pathway inactivation.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is one of the most prevalent malignant diseases in the urinary system with more than 140,000 related deaths annually. Ubiquitination-deubiquitination homeostasis is an important factor in ccRCC progression; ubiquitin-specific peptidase 53 (USP53) belongs to the family of deubiquitinating enzymes, but its functions are rarely reported. METHODS: Databases obtained from GEO and TCGA were analyzed to reveal the role of USP53 in ccRCC. CCK-8/BrdU and EDU assays were used to detect the proliferation of ccRCC after USP53 overexpression or knockdown. A tumor xenograft experiment was used to verify the effect of the proliferation of ccRCC after USP53 knockdown. Transwell assays were used to detect the metastasis of ccRCC after USP53 overexpression or knockdown. RNA sequencing and western blot analysis were employed to detect the change in genes after USP53 overexpression and knockdown. Then we tested the effect of USP53 on IκBα protein stability through western blot analysis. Detect the effect of USP53 on IκBα ubiquitination in vitro by immunoprecipitation method. RESULTS: USP53 expression was downregulated in ccRCC tissues and USP53 expression was significantly negatively correlated with the tumor progression and clinical prognosis. The ability of growth and metastasis of ccRCC was inhibited after USP53 overexpression. In addition, USP53 knockdown promoted ccRCC growth and metastasis. Moreover, USP53 knockdown promoted the ability of clone formation of ccRCC in vivo. NF-κB signaling pathway significantly enriched and downregulated in USP53 overexpressed cells, and genes in the NF-κB pathway (such as IL1B, CXCL1-3, RELA, RELB, etc.) were obviously downregulated in USP53 overexpressed cells. USP53 overexpression decreased the phosphorylation of IKKß and P65 in both Caki-1 and 786-O cells, and the expression of IκBα was increased. Phosphorylation of IKKß and P65 was increased in both Caki-1 and 786-O cells after USP53 knockdown. As the expression of USP53 increases, the protein expression of IκBα was also gradually increased and USP53 reduced the ubiquitination of IκBα. CONCLUSION: In summary, our data indicate that USP53 inhibits the inactivation of the NF-κB pathway by reducing the ubiquitination of IκBα to further inhibit ccRCC proliferation and metastasis. These findings may help understand the pathogenesis of ccRCC and introduce new potential therapeutic targets for kidney cancer patients.

The "Traditional Chinese medicine regulating liver regeneration" treatment plan for reducing mortality of patients with hepatitis B-related liver failure based on real-world clinical data.

On the basis of real-world clinical data, the study aimed to explore the effect and mechanisms of the treatment plan of "traditional Chinese medicine (TCM) regulating liver regeneration." A total of 457 patients with HBV-related liver failure were retrospectively collected. The patients were divided into three groups: the modern medicine control group (MMC group), patients treated with routine medical treatment; the control group combining traditional Chinese and Western medicine (CTW), patients treated with routine medical treatment plus the common TCM formula; and the treatment group of "TCM regulating liver regeneration" (RLR), patients treated with both routine medical treatment and the special TCM formula of RLR. After 8 weeks of treatment, the mortality of patients in the RLR group (12.31%) was significantly lower than those in the MMC (50%) and CTW (29.11%) groups. Total bilirubin level significantly decreased and albumin increased in the RLR group when compared with the MMC and CTW groups (P < 0.05). In addition, there were significant differences in the expression of several cytokines related to liver regeneration in the RLR group compared with the MMC group. RLR treatment can decrease jaundice, improve liver function, and significantly reduce the mortality in patients with HBV-related liver failure. The mechanism may be related to the role of RLR treatment in influencing cytokines related to liver regeneration.

High-Performance Photochromic Hydrogels for Rewritable Information Record.

Rewritable information record materials usually demand not only reversibly stimuli-responsive ability, but also strong mechanical properties. To achieve one photochromic hydrogel with super-strong mechanical strength, hydrophobic molecule spiropyran (SP) has been introduced into a copolymer based on ion-hybrid crosslink. The hydrogels exhibit both photoinduced reversible color changes and excellent mechanical properties, i.e., the tensile stress of 3.22 MPa, work of tension of 12.8 MJ m-3 , and modulus of elasticity of 8.6 MPa. Moreover, the SP-based Ca2+ crosslinked hydrogels can be enhanced further when exposed to UV-light via ionic interaction coordination between Ca2+ , merocyanine (MC) with polar copolymer chain. In particular, hydrogels have excellent reversible conversion behavior, which can be used to realize repeatable writing of optical information. Thus, the novel design is demonstrated to support future applications in writing repeatable optical information, optical displays, information storage, artificial intelligence systems, and flexible wearable devices.

miR-4500 suppresses cell proliferation and migration in bladder cancer via inhibition of STAT3/CCR7 pathway.

Bladder cancer (BC) is a prevalent type of cancer that occurs in human urinary system threatening the human health. microRNA-4500 (miRNA-4500) is a novel miRNA that serves as a potential biomarker in several types of cancers. However, the in-depth molecular mechanism of miR-4500 in BC has not yet been fully elucidated. Quantitative real-time polymerase chain reactionq and Western blot analysis were applied to analyze the expressions of miR-4500, STAT3, and C-C chemokine receptor 7 (CCR7). Gain-of-function assays involving Cell Counting Kit-8, 5'-ethynyl-2'-deoxyuridine incorporation assay, and Transwell were employed to evaluate miR-4500 function in cell proliferation and migration. Moreover, chromatin immunoprecipitation, RNA immunoprecipitation, and luciferase reporter assay were performed to explore the molecular mechanism underlying function of miR-4500. We found the downregulation of miR-4500 in BC cells, and ectopic expression of miR-4500 hampered cell proliferation, migration, and epithelial-to-mesenchymal transition. Importantly, miR-4500 directly targeted STAT3 3'-untranslated region, leading to repression on STAT3 expression. Intriguingly, STAT3 transcriptionally regulated CCR7. Rescue experiments validated the presence of miR-4500/STAT3/CCR7 axis in control of BC growth and progression. Our data highlighted miR-4500 as a potent cancericidal gene in BC, and might provide a theoretical grounding for development of target-oriented therapies of patients afflicted with BC.

Prognostic significance of platelet-to-lymphocyte ratio in patients with nasopharyngeal carcinoma: a meta-analysis.

Aim: Several studies reported the association of platelet-to-lymphocyte ratio (PLR) and prognosis in nasopharyngeal carcinoma (NPC), but the results remain controversial. Therefore, we investigated the prognostic value of PLR in NPC through meta-analysis. Materials & methods: A comprehensive literature search of PubMed, Embase and Web of Science was performed. Results: A total of 9 studies comprising of 3459 patients with NPC were included. The data demonstrated that an increased PLR predicted poor overall survival, progression-free survival and distant metastasis-free survival. There was no significant association between PLR and sex, age, T stage, N stage, tumor node metastasis (TNM) stage or intensity-modulated radiotherapy. Conclusion: This meta-analysis revealed that PLR might be a potential predicative biomarker of poor prognosis in patients with NPC.

Diwu Yanggan Modulates the Wnt/ß-catenin Pathway and Inhibits Liver Carcinogenesis Signaling in 2-AAF/PH Model Rats.

The activation of the Wnt/ß-catenin signaling pathway in oval cells after liver injury is implicated in hepatocarcinogenesis. Diwu Yanggan capsule is a Chinese herbal medicine that has been used for treating liver disorder. The present study aimed to examine the mechanism by which Diwu Yanggan inhibits liver carcinogenesis, and the involvement of the Wnt/ß-catenin signaling pathway. Diwu Yanggan capsule was administered to 2-acetaminofluorene/partial hepatectomy (2-AAF/PH) rats, a murine model of liver injury. The biomarkers of oval cells and key proteins in the Wnt/ß-catenin signaling pathway were assessed on postoperative day 8, 10, 14, 17, 19 and 22. The results showed that treatment with Diwu Yanggan was associated with reduced expression of oval cell and stem cell biomarkers in the 2-AAF/PH animals. The expression pattern of key proteins in the Wnt/ß-catenin pathway was altered in Diwu Yanggan-treated animals, indicating that the Diwu Yanggan treatment accelerated the activation of the Wnt/ß-catenin pathway in the initial stage and contributed to its deactivation in the later stage. Histological findings indicated that hepatocyte proliferation was suppressed in Diwu Yanggan-treated animals, compared with untreated 2-AAF/PH animals. Taken together, Diwu Yanggan capsule may reduce the risk of hepatocarcinogenesis by modulating the Wnt/ß-catenin signaling pathway.

Ubiquitin-specific peptidase 46 (USP46) suppresses renal cell carcinoma tumorigenesis through AKT pathway inactivation.

USP46, a member of the ubiquitin-specific protease family, plays essential roles in cancer cell proliferation and metastasis and is used as a candidate target for cancer therapeutics. However, the effects of USP46 on renal cell carcinoma (RCC) and its underlying molecular mechanism remain unknown. In this study, the predictive and prognostic relevance of USP46 in RCC, patient-derived primary tissues, and normal liver tissues obtained from the TCGA dataset were analyzed for the USP46 mRNA levels or prognostic relevance. Gain-of-function or loss-of-function assays were used to evaluate the vital roles of USP46 in tumor cell proliferation and cell migration. As a result, the USP46 expression level in RCC is highly decreased compared to normal tissues, and the Kaplan-Meier curve showed that USP46 high expression patients had good prognoses. Functionally, the forced expression of USP46 significantly restrained tumor cell proliferation, colony formation, and cell migration. The shRNA mediated USP46 knockdown cells exhibited the opposite results. We further showed that ectopically expressed USP46 obviously inhibited the AKT signaling pathway in cancer cells, while USP46 depletion caused a dramatic increase in AKT activity reflected by phosphorylation in the serine and threonine residues of AKT or downstream p70S6K1. Importantly, MK2206, a specific AKT inhibitor, completely counteracted the effects on cell proliferation, cell migration, and AKT activity in the USP46 depletion cells. We thus revealed a novel mechanism of USP46 regulation in RCC, and our data indicate that USP46 is a tumor suppressor in RCC via AKT signaling pathway inactivation.

Integrated analysis of a competing endogenous RNA network in renal cell carcinoma using bioinformatics tools.

BACKGROUND: Circular RNAs (circRNAs) are known to be closely involved in tumorigenesis and cancer progression. Nevertheless, their function and underlying mechanisms in renal cell carcinoma (RCC) remain largely unknown. The aim of the present study was to explore their expression, functions, and molecular mechanisms in RCC. METHODS: We downloaded the circRNA expression profiles from Gene Expression Omnibus (GEO) database, and RNA expression profiles from The Cancer Genome Atlas (TCGA) database. A ceRNA network was constructed based on circRNA-miRNA pairs and miRNA-mRNA pairs. Interactions between proteins were analyzed using the STRING database, and hub genes were identified using the cytoHubba app. We also constructed a circRNA-miRNA-hub gene regulatory module. Functional and pathway enrichment analyses were conducted using "DAVID 6.8" and R package "clusterProfiler". RESULTS: About 6 DEcircRNAs, 17 DEmiRNAs, and 134 DEmRNAs were selected for the construction of ceRNA network of RCC. Protein-protein interaction network and module analysis identified 8 hub genes. A circRNA-miRNA-hub gene sub-network was constructed based on 3 DEcircRNAs, 4 DEmiRNAs, and 8 DEmRNAs. GO and KEGG pathway analysis indicated the possible association of DEmRNAs with RCC onset and progression. CONCLUSIONS: These findings together provide a deeper understanding of the pathogenesis of RCC and suggest potential therapeutic targets.