UDP-glucose 6-dehydrogenase lessens sorafenib sensitivity via modulating unfolded protein response.

As the first-generation targeted therapy, sorafenib remains an effective single-drug treatment for advanced hepatocellular carcinoma (HCC). Unfortunately, the existence of resistance restricts the long-term benefit of patients. UDP-glucose 6-dehydrogenase (UGDH) is the key enzyme of glucuronic acid metabolism which was largely reported in mediating drug systemic elimination. In this study, we explore its critical role in regulating sorafenib sensitivity. Here we find sorafenib exposure could activate glucuronic acid metabolism, accompanied with the elevated expression of UGDH. Interference with the route by silencing UGDH could boost HCC cells sensitivity to sorafenib. Meanwhile, the analysis of HCC patients with sorafenib treatment displayed that low UGDH expression predicted superior prognosis. Further screening assay suggested that unfolded protein response (UPR) involves in UGDH silencing-mediated apoptosis. Xenograft model confirmed that combined UGDH intervention could significantly improve sorafenib efficacy. Our results reveal the impact of sorafenib exposure on glucuronic acid metabolism reprogramming and provide UGDH as a promising target to improve sorafenib efficacy.

Antipsychotic-induced gastrointestinal hypomotility and the alteration in gut microbiota in patients with schizophrenia.

AIM: Gut microbiota play an important role in the pathogenesis of gut hypomotility and are critical for the production of the intestinal immune system and the maintenance of the intestinal homeostasis. Patients with psychotic disorders are at a high risk of antipsychotic-induced constipation. However, the mechanisms might be more than neurotransmission properties of antipsychotics. METHODS: We recruited a total of 45 patients with constipation according to Rome IV criteria and objective test for colonic motility and the other 45 gender- and age-matching patients without constipation and investigated their differences in composition of gut microbiota. The demographic and serum metabolic indices were collected. The subjective constipation assessment scale (CAS) and the Bristol stool classification (BSS) were also used to evaluate the degree of constipation in both groups. The fecal samples were analysed using the 16S rRNA gene sequencing. RESULTS: The constipation group had a significantly increased alpha diversity in Observed species, Chao 1, and ACE as compared to the non-constipation group. At the phylum levels, the relative abundances of Bacteroidetes and Fusobacteria decreased significantly, while those of Firmicutes, Verrucomicrobia, and Synergistetes increased significantly in the constipation group. At the genus level, the relative abundances of Christensenella and Desulfovibrio were higher in the constipation group. The α-diversity indices of gut microbiota were correlated positively with the levels of serum total bile acid and correlated negatively with BSS scores. The BSS scores were positively correlated with the relative abundance of Bacteroidetes but negatively correlated with the relative abundance of Firmicutes. PICRUSt analysis revealed the potential metabolic pathways of lipopolysaccharide, vitamin B6, riboflavin, pyruvate, and propionate functions. CONCLUSIONS: The alternation of the gut microbiota in schizophrenia patients with antipsychotic-induced constipation indicates antipsychotic agents might affect gastrointestinal motility via varying microbiome-related metabolites, and the specific bacteria, such as Synergistetes which might act as an anti-inflammatory factor in the healthy human gut, related to colonic transit motility seem inconsistent to the findings from previous literature in gastroenterology. However, the causal effects are still unknown. Our study provides a new possibility to understand the mechanisms of antipsychotic-induced constipation.

C-Type Lectin-Like Receptor 2 Suppresses AKT Signaling and Invasive Activities of Gastric Cancer Cells by Blocking Expression of Phosphoinositide 3-Kinase Subunits.

BACKGROUND & AIMS: C-type lectin-like receptor 2 (CLEC2) is a transmembrane receptor expressed on platelets and several hematopoietic cells. CLEC2 regulates platelet aggregation and the immune response. We investigated its expression and function in normal and transformed gastric epithelial cells from human tissues. METHODS: We performed tissue microarray analyses of gastric carcinoma samples collected from 96 patients who underwent surgery at Zhongshan Hospital of Fudan University in Shanghai, China and performed real-time polymerase chain reaction assays from an independent group of 60 patients; matched nontumor gastric mucosa tissues were used as the control. Full-length and mutant forms of CLEC2 were expressed in gastric cancer cell line (MGC80-3), or CLEC2 protein was knocked down using small-hairpin RNAs in gastric cancer cell lines (NCI-N87 and AGS). CLEC2 signaling was stimulated by incubation of cells with recombinant human podoplanin or an antibody agonist of CLEC2; cell migration and invasion were assessed by transwell and wound-healing assays. Immunoblot, immunofluorescence microscopy, and real-time polymerase chain reaction assays were used to measure expression of markers of the epithelial to mesenchymal transition and activation of signaling pathways. Immunoprecipitation experiments were performed with an antibody against spleen tyrosine kinase (SYK). Cells were injected into lateral tail vein of BALB/C nude mice; some mice were also given injections of the phosphoinositide 3-kinase (PI3K) inhibitor LY294002. Lung and liver tissues were collected and analyzed for metastases. RESULTS: Levels of CLEC2 were higher in nontumor gastric mucosa (control) than in gastric tumor samples. Levels of CLEC2 protein in gastric tumor tissues correlated with depth of tumor invasion, metastasis to lymph node, tumor TNM stage, and 5-year survival of patients. Activation of CLEC2 in gastric cancer cells reduced their invasive activities in vitro and expression of epithelial to mesenchymal transition markers; these tumor-suppressive effects of CLEC2 required SYK. CLEC2 and SYK interacted physically, and SYK maintained the stability of CLEC2 in cells. AGS cells with CLEC2 knockdown had increased levels of phosphorylated AKT and glycogen synthase kinase-3 beta, increased expression of Snail, reduced levels of E-cadherin, and formed more metastases in mice than AGS cells that expressed CLEC2; these knockdown changes were prevented by the PI3K inhibitor LY294002. Activation of CLEC2 in AGS cells reduced protein and messenger RNA levels of PI3K subunits p85 and p110; this effect was blocked by SYK inhibitor R406. Levels of CLEC2 and SYK proteins and messenger RNAs correlated in gastric tumor samples. CONCLUSIONS: CLEC2 suppresses metastasis of gastric cancer cells injected into mice, and prevents activation of AKT and glycogen synthase kinase-3 beta signaling, as well as invasiveness and expression of epithelial to mesenchymal transition markers in gastric cancer cell lines. CLEC2 prevents expression of PI3K subunits, in a SYK-dependent manner.

Membrane-bound heat shock proteins facilitate the uptake of dying cells and cross-presentation of cellular antigen.

Heat shock proteins (HSPs) were originally identified as stress-responsive proteins and serve as molecular chaperones in different intracellular compartments. Translocation of HSPs to the cell surface and release of HSPs into the extracellular space have been observed during the apoptotic process and in response to a variety of cellular stress. Here, we report that UV irradiation and cisplatin treatment rapidly induce the expression of membrane-bound Hsp60, Hsp70, and Hsp90 upstream the phosphatidylserine exposure. Membrane-bound Hsp60, Hsp70 and Hsp90 could promote the release of IL-6 and IL-1ß as well as DC maturation by the evaluation of CD80 and CD86 expression. On the other hand, Hsp60, Hsp70 and Hsp90 on cells could facilitate the uptake of dying cells by bone marrow-derived dendritic cells. Lectin-like oxidized LDL receptor-1 (LOX-1), as a common receptor for Hsp60, Hsp70, and Hsp90, is response for their recognition and mediates the uptake of dying cells. Furthermore, membrane-bound Hsp60, Hsp70 and Hsp90 could promote the cross-presentation of OVA antigen from E.G7 cells and inhibition of the uptake of dying cells by LOX-1 decreases the cross-presentation of cellular antigen. Therefore, the rapid exposure of HSPs on dying cells at the early stage allows for the recognition by and confers an activation signal to the immune system.

Integrated glycomic analysis of ovarian cancer side population cells.

BACKGROUND: Ovarian cancer is the most lethal gynecological malignancy due to its frequent recurrence and drug resistance even after successful initial treatment. Accumulating scientific evidence indicates that subpopulations of cancer cells with stem cell-like properties, such as so-called side population (SP) cells, are primarily responsible for these recurrences. A better understanding of SP cells may provide new clues for detecting and targeting these cancer-initiating cells and ultimately help to eradicate cancer. Changes in glycosylation patterns are remarkable features of SP cells. Here, we isolated SP cells from ovarian cancer cell lines and analyzed their glycosylation patterns using multiple glycomic strategies. METHODS: Six high-grade serous ovarian cancer cell lines were used for SP cell isolation. Among them, HO8910 pm, which contained the highest proportion of SP cells, was used for glycomic analysis of SP cells. Cell lysate of SP cells and main population cells was applied to lectin microarray and mass spectrometry for glycan profiling. Differently expressed glycan structures were further verified by lectin blot, flow cytometry, and real-time PCR analysis of their relevant enzymes. RESULTS: Expression of core fucosylated N-glycan and tumor-associated Tn, T and sT antigens were increased in SP cells. By contrast, SP cells exhibited decreased hybrid glycan, α2,3-linked sialic glycan and multivalent sialyl-glycan. CONCLUSIONS: Glycan structures, such as Tn, T, sT antigens, and core fucosylation may serve as biomarkers of ovarian cancer stem cells.

Elevated Expression of Calpain-4 Predicts Poor Prognosis in Patients with Gastric Cancer after Gastrectomy.

Calpain-4 belongs to the calpain family of calcium-dependent cysteine proteases, and functions as a small regulatory subunit of the calpains. Recent evidence indicates that calpain-4 plays critical roles in tumor migration and invasion. However, the roles of calpain-4 in gastric tumorigenesis remain poorly understood. Herein, we examined calpain-4 expression by immunohistochemical staining on tissue microarrays containing tumor samples of 174 gastric cancer patients between 2004 and 2008 at a single center. The Kaplan-Meier method was used to compare survival curves, and expression levels were correlated to clinicopathological factors and overall survival. Our data demonstrated that calpain-4 was generally increased in gastric cancer cell lines and primary tumor tissues. High expression of calpain-4 was positively associated with vessel invasion, lymph node metastasis, and advanced TNM (Tumor Node Metastasis) stage. Multivariate analysis identified calpain-4 as an independent prognostic factor for poor prognosis. A predictive nomogram integrating calpain-4 expression with other independent prognosticators was constructed, which generated a better prognostic value for overall survival of gastric cancer patients than a TNM staging system. In conclusion, calpain-4 could be regarded as a potential prognosis indicator for clinical outcomes in gastric cancer.

PKCα promotes generation of reactive oxygen species via DUOX2 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains the second leading cause of cancer-related death worldwide, and elevated rates of reactive oxygen species (ROS) have long been considered as a hallmark of almost all types of cancer including HCC. Protein kinase C alpha (PKCα), a serine/threonine kinase among conventional PKC family, is recognized as a major player in signal transduction and tumor progression. Overexpression of PKCα is commonly observed in human HCC and associated with its poor prognosis. However, how PKCα is involved in hepatocellular carcinogenesis remains not fully understood. In this study, we found that among the members of conventional PKC family, PKCα, but not PKCßI or ßII, promoted ROS production in HCC cells. PKCα stimulated generation of ROS by up-regulating DUOX2 at post-transcriptional level. Depletion of DUOX2 abrogated PKCα-induced activation of AKT/MAPK pathways as well as cell proliferation, migration and invasion in HCC cells. Moreover, the expression of DUOX2 and PKCα was well positively correlated in both HCC cell lines and patient samples. Collectively, our findings demonstrate that PKCα plays a critical role in HCC development by inducing DUOX2 expression and ROS generation, and propose a strategy to target PKCα/DUOX2 as a potential adjuvant therapy for HCC treatment.

Functional expression of the Fc-fused extracellular domains of group II membrane proteins.

The complicated delivery mechanism of group II membrane proteins makes it difficult to decide the fusion pattern of their extracellular domains (ECDs) with Fc moiety. In this study, we compared the expression of ECDs of three group II membrane proteins including CLEC-2, Dectin-1, and LOX-1 by fusion of Fc moiety. We found that the pattern of ECD-Fc fusion order produced the functionally active recombinant proteins while the pattern of Fc-ECD fusion order led to the altered glycosylation which abolished the binding of these proteins with their ligands. Meanwhile, our results indicated that the secretion of mouse Fc (mFc)-fused ECD of CLEC-2 was more efficient than that of rabbit Fc (rFc)-fused protein, while rFc moiety was more sensitive for detection compared with mFc moiety. Altogether, we provide a favorable fusion pattern of Fc moiety with the ECDs of group II transmembrane proteins.

Brain-Type Glycogen Phosphorylase (PYGB) in the Pathologies of Diseases: A Systematic Review.

Glycogen metabolism is a form of crucial metabolic reprogramming in cells. PYGB, the brain-type glycogen phosphorylase (GP), serves as the rate-limiting enzyme of glycogen catabolism. Evidence is mounting for the association of PYGB with diverse human diseases. This review covers the advancements in PYGB research across a range of diseases, including cancer, cardiovascular diseases, metabolic diseases, nervous system diseases, and other diseases, providing a succinct overview of how PYGB functions as a critical factor in both physiological and pathological processes. We present the latest progress in PYGB in the diagnosis and treatment of various diseases and discuss the current limitations and future prospects of this novel and promising target.

E3 ubiquitin ligase CHIP interacts with transferrin receptor 1 for degradation and promotes cell proliferation through inhibiting ferroptosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the major form of liver malignancy with high incidence and mortality. Identifying novel biomarkers and understanding regulatory mechanisms underlying the development and progression of HCC are critical for improving diagnosis, treatment and patient outcomes. Carboxyl terminus of Hsc-70-interacting protein (CHIP) is a well-described U-box-type E3 ubiquitin ligase which promotes the ubiquitination and degradation of numerous tumor-associated proteins. Recent studies have shown that CHIP can play as a tumor-suppressor gene or an oncogene in different kinds of malignancies. To date, the function and mechanism of CHIP in hepatocellular carcinoma remains largely unknown. Based on TCGA data, we found that compared with high CHIP expression, the overall survival of HCC patients with low expression of CHIP was better. In addition, CHIP overexpression markedly enhanced HCC cell proliferation and colony formation. Conversely, knockdown of CHIP restrained the proliferation and colony formation of HCC cells. Meanwhile, knockdown of CHIP decreased mitochondrial cristae or ruptured outer mitochondrial membrane, promoted the accumulation of Fe2+ and ferroptosis of HCC cells. Further research for the first time confirmed that CHIP interacts and degrades transferrin receptor 1 (TfR1) by ubiquitin-proteasome pathway, which leads to the inhibition of ferroptosis and promotes the proliferation of HCC cells. The analysis of proteomics data from CPTAC revealed a negative correlation between CHIP and TfR1 protein expression levels in HCC. These findings indicate that CHIP acts as a negative modulator of ferroptosis and functions as an oncogene in HCC.

Using transfixion irrigation with negative pressure drainage (TINPD) minimally invasive to manage infratemporal fossa (ITF) abscess.

RATIONALE: The treatment of abscess in the infratemporal space is still controversial and bedside and operative intraoral drainage is often used to resolve the abscess. However, it can be difficult to control the infection quickly.[1] In this report, the authors present a new technique of using transfixion irrigation with negative pressure drainage for minimally invasive management of infratemporal fossa abscess. PATIENT CONCERNS: A 45-year-old man with type 2 diabetes complained of painful swelling and trismus in the right lower facial region for 10 days. The patient was weak, with mild anxiety, and gradually aggravated. DIAGNOSES: The patient was misdiagnosed and received dental pulp treatment for the right mandibular first molar and was given oral cefradine capsules (500 mg 3 times per day). Computed tomography scan and puncture revealed an abscess in the infratemporal fossa. INTERVENTION: The authors used transfixion irrigation with negative pressure drainage from different directions to reach the abscess cavity. Saline solution was infused through 1 tube and allowed to flow out through the other tube to flush out the pus and debris from the abscess. OUTCOME: On day 9, the drainage tube was removed and the patient was discharged. One week later, the patient was followed up in the outpatient clinic and the impacted mandibular third molar was removed. This technique is less invasive and leads to faster recovery times and fewer complications. LESSONS SUBSECTIONS: The report highlights the importance of proper preoperative evaluation, using a thoracic drainage tube as soon as possible, and continuous flushing. A double-lumen drainage tube with a suitable diameter and combined flushing should be designed for future reference. Moreover, the use of drugs can effectively eliminate emboli formation, allowing for faster and more minimally invasive control and removal of the infection.[2].

The role of the gut microbiome in weight-gain in schizophrenia patients treated with atypical antipsychotics: Evidence based on altered composition and function in a cross-sectional study.

OBJECTIVES: We aimed to explore the interconnection between the weight-gain in schizophrenia patients with atypical antipsychotic treatment and gut microbiome. METHODS: This study employed a cross-sectional design, encompassing a total of 88 schizophrenia patients with long-term atypical antipsychotic treatment. The 16S rRNA gene sequencing was used to identify gut microbiome contents. RESULTS: No significant differences in alpha diversity between normal-weight and overweight schizophrenia treated with atypical antipsychotics. The beta diversity analysis showed that overweight patients clustered tightly while normal-weight patients clustered widely. For taxonomic composition, overweight patients had a lower relative abundance in Porphyromonadaceae at family level and Butyrivibrio at genus level, but higher relative abundance in Ruminococcus2 and Clostridium_XIVa at genus level than normal-weight patients. Function prediction revelated that four pathways (including Cell cycle, Non-homologous end-joining, Vibrio cholerae infection and Meiosis-yeast) were significantly different between groups. Correlation analysis indicated that Klebsiella, Butyrivibrio, Unassigned, Methanosphaera, Holdemania, Anaerotruncus were negatively, while Veillonella was positively correlated with BMI in patients. CONCLUSION: Our findings offer evidence that perturbations in the gut microbiome composition, encompassing taxa such as Porphyromonadaceae, Butyrivibrio, Ruminococcus2, and Clostridium_XIVa, in conjunction with distinct functional pathways including Cell cycle, Non-homologous end-joining, Vibrio cholerae infection, and Meiosis-yeast, might contribute to the weight-gain in schizophrenia treated with atypical antipsychotics.

Serum Metabolic Profile in Schizophrenia Patients With Antipsychotic-Induced Constipation and Its relationship With Gut Microbiome.

BACKGROUND AND HYPOTHESIS: Antipsychotics (APs), the cornerstone of schizophrenia treatment, confer a relatively high risk of constipation. However, the mechanisms underpinning AP-induced constipation are poorly understood. Thus, we hypothesized that (1) schizophrenia patients with AP-induced constipation have distinct metabolic patterns; (2) there is more than one mechanism at play in producing this adverse drug effect; and (3) AP-associated changes in the gut microbiome are related to the altered metabolic profiles. STUDY DESIGN: Eighty-eight schizophrenia patients, including 44 with constipation (C) and 44 matched patients without constipation (NC), were enrolled in this study. Constipation was diagnosed by Rome IV criteria for constipation and colonic transit time using radiopaque markers (ROMs) while severity was evaluated with the Bristol Stool Form Scale (BSS) and Constipation Assessment Scale (CAS). Fasting blood samples were drawn from all participants and were subjected to non-targeted liquid chromatography-mass spectrometry (LC-MS) metabolomic analysis. STUDY RESULTS: Eleven metabolites were significantly altered in AP-induced constipation which primarily disturbed sphingolipid metabolism, choline metabolism, and sphingolipid signaling pathway (P value < .05, FDR < 0.05). In the C group, changes in the gut bacteria showed a certain degree of correlation with 2 of the significantly altered serum metabolites and were associated with alterations in choline metabolism. CONCLUSIONS: Our findings indicated that there were disturbances in distinct metabolic pathways that were associated with AP-induced constipation. In addition, this study presents evidence of a link between alterations in the gut microbiome and host metabolism which provides additional mechanistic insights on AP-induced constipation.

AHSA1 is a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma.

BACKGROUND: Currently, multiple myeloma (MM) is still an incurable plasma cell malignancy in urgent need of novel therapeutic targets and drugs. METHODS: Bufalin was known as a highly toxic but effective anti-cancer compound. We used Bufalin as a probe to screen its potential targets by proteome microarray, in which AHSA1 was the unique target of Bufalin. The effects of AHSA1 on cellular proliferation and drug resistance were determined by MTT, western blot, flow cytometry, immunohistochemistry staining and xenograft model in vivo. The potential mechanisms of Bufalin and KU-177 in AHSA1/HSP90 were verified by co-immunoprecipitation, mass spectrometry, site mutation and microscale thermophoresis assay. RESULTS: AHSA1 expression was increased in MM samples compared to normal controls, which was significantly associated with MM relapse and poor outcomes. Furthermore, AHSA1 promoted MM cell proliferation and proteasome inhibitor (PI) resistance in vitro and in vivo. Mechanism exploration indicated that AHSA1 acted as a co-chaperone of HSP90A to activate CDK6 and PSMD2, which were key regulators of MM proliferation and PI resistance respectively. Additionally, we identified AHSA1-K137 as the specific binding site of Bufalin on AHSA1, mutation of which decreased the interaction of AHSA1 with HSP90A and suppressed the function of AHSA1 on mediating CDK6 and PSMD2. Intriguingly, we discovered KU-177, an AHSA1 selective inhibitor, and found KU-177 targeting the same site as Bufalin. Bufalin and KU-177 treatments hampered the proliferation of flow MRD-positive cells in both primary MM and recurrent MM patient samples. Moreover, KU-177 abrogated the cellular proliferation and PI resistance induced by elevated AHSA1, and decreased the expression of CDK6 and PSMD2. CONCLUSIONS: We demonstrate that AHSA1 may serve as a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma.

Mismatch Repair Deficiency and Microsatellite Instability in Triple-Negative Breast Cancer: A Retrospective Study of 440 Patients.

PURPOSE: To investigate the status of mismatch repair (MMR) and microsatellite instability (MSI) in triple-negative breast cancer (TNBC) and to examine correlations between MMR/MSI status and clinicopathological parameters. METHODS: We retrospectively collected tissue samples from 440 patients with TNBC and constructed tissue microarrays. Protein expression of MLH1, MSH2, MSH6, and PMS2 was detected by immunohistochemistry (IHC). We also analyzed 195 patient samples using MSI polymerase chain reaction (PCR) testing. Correlations between MSI status and clinicopathological parameters and prognosis were analyzed. RESULTS: The median age of the cohort was 49 years (range: 24-90 years) with a median follow-up period of 68 months (range: 1-170 months). All samples were positive for MLH1, MSH2, MSH6, and PMS2, except for one sample identified as MMR-deficient (dMMR) by IHC, with loss of MSH2 and intact MSH6 expression. MSI PCR revealed no case with high-frequency MSI (MSI-H), whereas 14 (7.2%) and 181 (92.8%) samples demonstrated low-frequency and absence of MSI events, respectively. The dMMR sample harbored low-frequency instability, as revealed by MSI PCR, and a possible EPCAM deletion in the tumor, as observed from next-generation sequencing. No correlations were detected between MMR or MSI status and clinicopathological parameters, programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) expression, or survival. CONCLUSIONS: The incidence of dMMR/MSI-H is extremely low in TNBC, and rare discordant MSI PCR/MMR IHC results may be encountered. Moreover, MMR/MSI status may be of limited prognostic value. Further studies are warranted to explore other predictive immunotherapy biomarkers for TNBC.

Steroid 5α-Reductase Type I Induces Cell Viability and Migration via Nuclear Factor-κB/Vascular Endothelial Growth Factor Signaling Pathway in Colorectal Cancer.

Colorectal cancer (CRC) is a common malignant tumor of the digestive system. Steroid 5α-reductase type I (SRD5A1), as an important part of the steroid metabolism, converts testosterone to dihydrotestosterone and regulates sex hormone levels, which accommodates tumor occurrence or development. However, the underlying molecular mechanism of SRD5A1 in CRC remains unclear. We compared SRD5A1 expression in CRC tissues with normal controls by immunohistochemistry and found that elevated SRD5A1 in CRC was relevant for poor patient prognosis. Furthermore, inducible downregulation of SRD5A1 by small hairpin RNA reduced cell viability, promoted cell cycle arrest, and induced cell apoptosis and cellular senescence of CRC cells, as well as attenuated cell migration ability. In the following experiments, we used dutasteride (an inhibitor of SRD5A1/2) to explore its inhibitory effect on the biological processes of CRC cells, as mentioned earlier. Further mechanism study demonstrated that the repression of SRD5A1 abolished the expression of p65 and vascular endothelial growth factor, suggesting that SRD5A1 might regulate cell viability and migration through nuclear factor-κB/vascular endothelial growth factor signaling pathway. Collectively, these findings implicate SRD5A1 acting as a novel biomarker for CRC diagnosis and prognosis and provide compelling evidence for the future evaluation of dutasteride as a promising candidate for CRC treatment.

Targeting MK2 Is a Novel Approach to Interfere in Multiple Myeloma.

MAPKAPK2 (MK2), the direct substrate of p38 MAPK, has been well-acknowledged as an attractive drug target for cancer therapy. However, few studies have assessed the functions of it in multiple myeloma (MM). In the present study, MK2 expression of MM patients was analyzed by gene expression profiling (GEP) and array-based comparative genomic hybridization (aCGH). Several experiments in vitro including MTT assay, Western blot and flow cytometry analysis were performed to identify the function of MK2 in MM. In addition, we conducted mouse survival experiments to explain the effects of MK2 on MM in vivo. mRNA level of MK2 and chromosomal gain of MK2 locus in MM cells significantly increased compared to normal samples. Furthermore, MM patients with high expression of MK2 were associated with a poor outcome. Follow-up studies showed that MK2 exerted a remarkably positive effect on MM cell proliferation and drug-resistance. Further exploration focusing on MK2 inhibitor IV revealed its inhibitory action on MM growth and drug-resistance, as well as improving survival in mouse models. In addition, a combination of MK2 inhibitor IV and the key MM therapeutic agents including bortezomib, doxorubicin, or dexamethasone facilitated curative effects on inhibiting MM cell proliferation. Taken together, our study reveals the clinical relevance of MK2 inhibition in MM and demonstrates that targeting MK2 may afford a new therapeutic approach to MM.

Rpn10 promotes tumor progression by regulating hypoxia-inducible factor 1 alpha through the PTEN/Akt signaling pathway in hepatocellular carcinoma.

The ubiquitin-proteasome pathway plays a pivotal role in tumor progression. Rpn10 is the major ubiquitin (Ub) receptor of the 26S proteasome. Mounting evidence shows that Rpn10 is associated with the progression of several tumor types. However, little is known regarding the mechanistic role of Rpn10 in hepatocellular carcinoma (HCC). In this study, we found that the upregulation of Rpn10 in HCC was associated with poor prognosis. The ectopic overexpression of Rpn10 increased HCC cell proliferation, whereas silencing Rpn10 expression resulted in decreased cell proliferation. Furthermore, we demonstrated that knockdown of Rpn10 induced cell cycle arrest at G1 phase in HCC cells. In addition, we found that Rpn10 increased cell proliferation via regulation of the PTEN/Akt pathways. Knockdown of Rpn10 induced suppression of cell proliferation could be reversed by overexpressing active Akt in HCC cells. Rpn10 directly promoted PTEN degradation through the ubiquitin-proteasome system. The transcription factor HIF1α directly bound to the Rpn10 promoter and increased its expression in HCC tissue. Moreover, we observed a significant correlation between HIF1α expression and Rpn10 levels in HCC patients and found that the combination of these two parameters was a more powerful predictor of poor prognosis than either parameter alone. Collectively, these findings highlight the molecular mechanism of Rpn10 expression in HCC and provide valuable information for cancer prognosis and treatment.

Downregulation of miR-218-5p promotes invasion of oral squamous cell carcinoma cells via activation of CD44-ROCK signaling.

The invasion front of oral squamous cell carcinoma (OSCC) harbors the most aggressive cells of the tumor and is critical for cancer invasion and metastasis. MicroRNAs (miRNAs) play important roles in OSCC progression. In this study, we modelled the OSCC invasion front on a microfluidic chip, and investigated differences in miRNA profiles between cells in the invasion front and those in the tumor mass by small RNA sequencing. We found that miR-218-5p was downregulated in invasion front cells and negatively regulates OSCC invasiveness by targeting the CD44-ROCK pathway. Thus, miR-218-5p may serve as a useful therapeutic target for OSCC. Moreover, invasion front cell isolation based-on microfluidic technology provided a useful strategy for cancer invasion study.