Targeting SLC22A5 fosters mitophagy inhibition-mediated macrophage immunity against septic acute kidney injury upon CD47-SIRPα axis blockade.

Efferocytosis of apoptotic neutrophils (PMNs) by macrophages is helpful for inflammation resolution and injury repair, but the role of efferocytosis in intrinsic nature of macrophages during septic acute kidney injury (AKI) remains unknown. Here we report that CD47 and signal regulatory protein alpha (SIRPα)-the anti-efferocytotic 'don't eat me' signals-are highly expressed in peripheral blood mononuclear cells (PBMCs) from patients with septic AKI and kidney samples from mice with polymicrobial sepsis and endotoxin shock. Conditional knockout (CKO) of SIRPA in macrophages ameliorates AKI and systemic inflammation response in septic mice, accompanied by an escalation in mitophagy inhibition of macrophages. Ablation of SIRPA transcriptionally downregulates solute carrier family 22 member 5 (SLC22A5) in the lipopolysaccharide (LPS)-stimulated macrophages that efferocytose apoptotic neutrophils (PMNs). Targeting SLC22A5 renders mitophagy inhibition of macrophages in response to LPS stimuli, improves survival and deters development of septic AKI. Our study supports further clinical investigation of CD47-SIRPα signalling in sepsis and proposes that SLC22A5 might be a promising immunotherapeutic target for septic AKI.

Alcohol dehydrogenase 1 is a tubular mitophagy-dependent apoptosis inhibitor against septic acute kidney injury.

Alcohol dehydrogenase 1 (ADH1) is an alcohol-oxidizing enzyme with poorlydefined biology. Here we report that ADH1 is highly expressed in kidneys of mice with lethal endotoxemia and is transcriptionally upregulated in tubular cells by lipopolysaccharide (LPS) stimuli through TLR4/NF-κB cascade. The Adh1 knockout (Adh1KO) mice with lethal endotoxemia displayed increased susceptibility to acute kidney injury (AKI) but not systemic inflammatory response. Adh1KO mice develop more severe tubular cell apoptosis in comparison to Adh1 wild-type (Adh1WT) mice during course of lethal endotoxemia. ADH1 deficiency facilitates the LPS-induced tubular cell apoptosis in a caspase-dependent manner. Mechanistically, ADH1 deficiency dampens tubular mitophagy that relies on PINK1-Parkin pathway characterized by the reduced membrane potential, reactive oxygen species (ROS) and release of fragmented mtDNA to cytosol. Kidney-specific overexpression of PINK1 and Parkin by adeno-associated viral vector 9 (AAV9) delivery ameliorates AKI exacerbation in Adh1KO mice with lethal endotoxemia. Our study supports the notion that ADH1 is critical for blockade of tubular apoptosis mediated by mitophagy, allowing the rapid identification and targeting of alcohol-metabolic route applicable to septic AKI.

Forward variable selection for random forest models.

Random forest is a popular prediction approach for handling high dimensional covariates. However, it often becomes infeasible to interpret the obtained high dimensional and non-parametric model. Aiming for an interpretable predictive model, we develop a forward variable selection method using the continuous ranked probability score (CRPS) as the loss function. eOur stepwise procedure selects at each step a variable that minimizes the CRPS risk and a stopping criterion for selection is designed based on an estimation of the CRPS risk difference of two consecutive steps. We provide mathematical motivation for our method by proving that in a population sense, the method attains the optimal set. In a simulation study, we compare the performance of our method with an existing variable selection method, for different sample sizes and correlation strength of covariates. Our method is observed to have a much lower false positive rate. We also demonstrate an application of our method to statistical post-processing of daily maximum temperature forecasts in the Netherlands. Our method selects about 10% covariates while retaining the same predictive power.

Fluid retention-associated adverse events in patients treated with BCR::ABL1 inhibitors based on FDA Adverse Event Reporting System (FAERS): a retrospective pharmacovigilance study.

OBJECTIVES: This study aimed to conduct a thorough analysis of fluid retention-associated adverse events (AEs) associated with BCR::ABL inhibitors. DESIGN: A retrospective pharmacovigilance study. SETTING: Food and Drug Administration Adverse Event Reporting System (FAERS) database for BCR::ABL inhibitors was searched from 1 January 2004 to 30 September 2021. MAIN OUTCOME MEASURES: Reporting OR (ROR) and 95% CI were used to detect the signals. ROR was calculated by dividing the odds of fluid retention event reporting for the target drug by the odds of fluid retention event reporting for all other drugs. The signal was considered positive if the lower limit of 95% CI of ROR was >1. The analysis was run only considering coupled fluid retention events/BCR::ABL inhibitors with at least three cases. RESULTS: A total of 97 823 reports were identified in FAERS. Imatinib had the most fluid retention signals, followed by dasatinib and nilotinib, while bosutinib and ponatinib had fewer signals. Periorbital oedema (ROR=24.931, 95% CI 22.404 to 27.743), chylothorax (ROR=161.427, 95% CI 125.835 to 207.085), nipple swelling (ROR=48.796, 95% CI 26.270 to 90.636), chylothorax (ROR=35.798, 95% CI 14.791 to 86.642) and gallbladder oedema (ROR=77.996, 95% CI 38.286 to 158.893) were the strongest signals detected for imatinib, dasatinib, nilotinib, bosutinib and ponatinib, respectively. Pleural effusion, pericardial effusion and pulmonary oedema were detected for all BCR::ABL inhibitors, with dasatinib having the highest RORs for pleural effusion (ROR=37.424, 95% CI 35.715 to 39.216), pericardial effusion (ROR=14.146, 95% CI 12.649 to 15.819) and pulmonary oedema (ROR=11.217, 95% CI 10.303 to 12.213). Patients aged ≥65 years using dasatinib, imatinib, nilotinib or bosutinib had higher RORs for pleural effusion, pericardial effusion and pulmonary oedema. Patients aged ≥65 years and females using imatinib had higher RORs for periorbital oedema, generalised oedema and face oedema. CONCLUSIONS: This pharmacovigilance study serves as a clinical reminder to physicians to be more vigilant for fluid retention-associated AEs with BCR::ABL inhibitors.

Auto- and paracrine rewiring of NIX-mediated mitophagy by insulin-like growth factor-binding protein 7 in septic AKI escalates inflammation-coupling tubular damage.

AIMS: Inflammation-coupling tubular damage (ICTD) contributes to pathogenesis of septic acute kidney injury (AKI), in which insulin-like growth factor-binding protein 7 (IGFBP-7) serves as a biomarker for risk stratification. The current study aims to discern how IGFBP-7 signalling influences ICTD, the mechanisms that underlie this process and whether blockade of the IGFBP-7-dependent ICTD might have therapeutic value for septic AKI. MATERIALS AND METHODS: In vivo characterization was carried out in B6/JGpt-Igfbp7em1Cd1165/Gpt mice subjected to cecal ligation and puncture (CLP). Transmission electron microscopy, immunofluorescence, flow cytometry, immunoblotting, ELISA, RT-qPCR and dual-luciferase reporter assays were used to determine mitochondrial functions, cell apoptosis, cytokine secretion and gene transcription. KEY FINDINGS: ICTD augments the transcriptional activity and protein secretion of tubular IGFBP-7, which enables an auto- and paracrine signalling via deactivation of IGF-1 receptor (IGF-1R). Genetic knockout (KO) of IGFBP-7 provides renal protection, improves survival and resolves inflammation in murine models of cecal ligation and puncture (CLP), while administering recombinant IGFBP-7 aggravates ICTD and inflammatory invasion. IGFBP-7 perpetuates ICTD in a NIX/BNIP3-indispensable fashion through dampening mitophagy that restricts redox robustness and preserves mitochondrial clearance programs. Adeno-associated viral vector 9 (AAV9)-NIX short hairpin RNA (shRNA) delivery ameliorates the anti-septic AKI phenotypes of IGFBP-7 KO. Activation of BNIP3-mediated mitophagy by mitochonic acid-5 (MA-5) effectively attenuates the IGFBP-7-dependent ICTD and septic AKI in CLP mice. SIGNIFICANCE: Our findings identify IGFBP-7 is an auto- and paracrine manipulator of NIX-mediated mitophagy for ICTD escalation and propose that targeting the IGFBP-7-dependent ICTD represents a novel therapeutic strategy against septic AKI.

Downregulation of circ-STK39 suppresses pancreatic cancer progression by sponging mir-140-3p and regulating TRAM2-mediated epithelial-mesenchymal transition.

BACKGROUND: Pancreatic cancer (PC) is amongst the most lethal gastrointestinal tumors, which is the seventh leading reason of cancer-related mortality worldwide. Previous studies have indicated that circular RNAs (circRNAs), which is a new type of endogenous noncoding RNA (ncRNA), can mediate tumor progression in diverse tumor types including PC. Whereas precise roles regarding circRNAs and their underlying regulatory mechanisms in PC remain unknown. METHODS: In the current study, we employed next generation sequencing (NGS) to characterize abnormally expressed circRNAs among PC tissues. Next, we assessed expression levels of one identified circRNA, circ-STK39, in PC cell lines and tissues. Then, using bioinformatics analysis, luciferase reporter, Transwell migration, EdU and CCK-8 assays, we examined the regulatory mechanisms and targets of circ-STK39. Finally, our group explored the circ-STK39 role in PC tumor growth and metastasis in vivo. RESULTS: Our team discovered that circ-STK39 expression increased in PC tissues and cells, suggesting that circ-STK39 may have a role in PC progression. Downregulation of circ-STK39 inhibited PC proliferation and migration. Bioinformatics and luciferase reporter outcomes demonstrated that TRAM2 and miR-140-3p were circ-STK39 downstream targets. TRAM2 overexpression reversed the miR-140-3p overexpression effects upon migration, proliferation and the epithelial-mesenchymal transition (EMT). CONCLUSION: In this regard, we showed that circ-STK39 downregulation led to decreased migration, proliferation and the EMT of PC via the miR-140-3p/TRAM2 axis.

EmotionBox: A music-element-driven emotional music generation system based on music psychology.

With the development of deep neural networks, automatic music composition has made great progress. Although emotional music can evoke listeners' different auditory perceptions, only few research studies have focused on generating emotional music. This paper presents EmotionBox -a music-element-driven emotional music generator based on music psychology that is capable of composing music given a specific emotion, while this model does not require a music dataset labeled with emotions as previous methods. In this work, pitch histogram and note density are extracted as features that represent mode and tempo, respectively, to control music emotions. The specific emotions are mapped from these features through Russell's psychology model. The subjective listening tests show that the Emotionbox has a competitive performance in generating different emotional music and significantly better performance in generating music with low arousal emotions, especially peaceful emotion, compared with the emotion-label-based method.

Tubule-mitophagic secretion of SerpinG1 reprograms macrophages to instruct anti-septic acute kidney injury efficacy of high-dose ascorbate mediated by NRF2 transactivation.

High-dose ascorbate confers tubular mitophagy responsible for septic acute kidney injury (AKI) amelioration, yet its biological roles in immune regulation remain poorly understood. Methods: The role of tubular mitophagy in macrophage polarization upon high-dose ascorbate treatment was assessed by fluorescence-activated cell sorter analysis (FACS) in vitro and by immunofluorescence in AKI models of LPS-induced endotoxemia (LIE) from Pax8-cre; Atg7 flox/flox mice. The underlying mechanisms were revealed by RNA-sequencing, gene set enrichment analysis (GSEA), luciferase reporter, chromatin immunoprecipitation (ChIP) and adeno-associated viral vector serotype 9 (AAV9) delivery assays. Results: High-dose ascorbate enables conversion of macrophages from a pro-inflammatory M1 subtype to an anti-inflammatory M2 subtype in murine AKI models of LIE, leading to decreased renal IL-1ß and IL-18 production, reduced mortality and alleviated tubulotoxicity. Blockade of tubular mitophagy abrogates anti-inflammatory macrophages polarization under the high-dose ascorbate-exposed coculture systems. Similar abrogations are verified in LIE mice with tubular epithelium-specific ablation of Atg7, where the high-dose ascorbate-inducible renal protection and survival improvement are substantially weaker than their control littermates. Mechanistically, high-dose ascorbate stimulates tubular secretion of serpin family G member 1 (SerpinG1) through maintenance of mitophagy, for which nuclear factor-erythroid 2 related factor 2 (NRF2) transactivation is required. SerpinG1 perpetuates anti-inflammatory macrophages to prevent septic AKI, while kidney-specific disruption of SerpinG1 by adeno-associated viral vector serotype 9 (AAV9)-short hairpin RNA (shRNA) delivery thwarts the anti-inflammatory macrophages polarization and anti-septic AKI efficacy of high-dose ascorbate. Conclusion: Our study identifies SerpinG1 as an intermediate of tubular mitophagy-orchestrated myeloid function during septic AKI and reveals a novel rationale for ascorbate-based therapy.

WD repeat domain 62 (WDR62) promotes resistance of colorectal cancer to oxaliplatin through modulating mitogen-activated protein kinase (MAPK) signaling.

WD repeat domain 62 (WDR62) is involved in embryonic brain growth through regulation of glial and neural cell populations. WDR62 is also implicated in the carcinogenesis of various cancers. The role of WDR62 in progression and chemoresistance of colorectal cancer (CRC) was investigated. Firstly, oxaliplatin-resistant CRC cells (HCT116/R and HT29/R) were sequentially exposed to an increasing concentration of oxaliplatin. The results showed that WDR62 was elevated in CRC tissues, and oxaliplatin resistance conferred up-regulation of WDR62 in CRC cells. Knockdown of WDR62 reduced cell proliferation and promoted the apoptosis of oxaliplatin-resistant CRC cells. Moreover, silencing of WDR62 increased fluorescence intensity of γH2AX, and decreased protein expression of p-DNA-PK and Rad51 in the oxaliplatin-resistant CRC cells. The protein expression of p-ERK, p-JNK, and p-p38 in oxaliplatin-resistant CRC cells were down-regulated by knockdown of WDR62. In conclusion, silencing of WDR62 suppressed oxaliplatin resistance and DNA damage repair of CRC cells through inactivation of MAPK signaling.

Effects of Stimulation Position and Frequency Band on Auditory Spatial Perception with Bilateral Bone Conduction.

Virtual sound localization tests were conducted to examine the effects of stimulation position (mastoid, condyle, supra-auricular, temple, and bone-anchored hearing aid implant position) and frequency band (low frequency, high frequency, and broadband) on bone-conduction (BC) horizontal localization. Non-individualized head-related transfer functions were used to reproduce virtual sound through bilateral BC transducers. Subjective experiments showed that stimulation at the mastoid gave the best performance while the temple gave the worst performance in localization. Stimulation at the mastoid and condyle did not differ significantly from that using air-conduction (AC) headphones in localization accuracy. However, binaural reproduction at all BC stimulation positions led to similar levels of front-back confusion (FBC), which were also comparable to that with AC headphones. Binaural BC reproduction with high-frequency stimulation led to significantly higher localization accuracy than with low-frequency stimulation. When transcranial attenuation (TA) was measured, the attenuation became larger at the condyle and mastoid, and increased at high frequencies. The experiments imply that larger TAs may improve localization accuracy but do not improve FBC. The present study indicates that the BC stimulation at the mastoid and condyle can effectively convey spatial information, especially with high-frequency stimulation.

Measurement and modeling of the mechanical impedance of human mastoid and condyle.

Bone conduction devices are used in audiometric tests, hearing rehabilitation, and communication systems. The mechanical impedance of the stimulated skull location affects the performance of the bone conduction devices. In the present study, the mechanical impedances of the mastoid and condyle were measured in 100 Chinese subjects aged from 22 to 67 years. The results show that the mastoid and condyle impedances within the same subject differ significantly and the impedance differences between subjects at the same stimulation position are mainly below the resonance frequency. The mechanical impedance of the mastoid is significantly influenced by age, and not related to gender or body mass index (BMI). While the mechanical impedance of the condyle is significantly affected by BMI, followed by gender, and not related to age. There are some differences in mastoid impedance between the Chinese and Western subjects. An analogy model predicts that the difference in mechanical impedance between the mastoid and condyle leads to a significant difference in the output force of the bone conduction devices. The results can be used to develop improved condyle and mastoid stimulators for the Chinese.

Effects of valsartan combined with α-lipoic acid on renal function in patients with diabetic nephropathy: a systematic review and meta-analysis.

BACKGROUND: Diabetic nephropathy (DN) is one of the most serious microvascular complications of diabetes, valsartan and α-lipoic acid alone or in combination has been used for the treatment of patients with DN. However, some results in these clinical reports were still controversial. The purpose of this study was to evaluate the efficacy of valsartan combined with α-lipoic acid on renal function in patients with DN. METHODS: We searched the electronic databases including PubMed, Sciencedirect, EMBASE, Cochrane library, Chinese national knowledge infrastructure (CNKI) and Wanfang databases, and the publication deadline was limited to January 2020. Randomized controlled trials (RCTs) evaluating the effects of valsartan combined with α-lipoic acid in DN patients were included. Pooled estimates were conducted using a fixed or random effect model. The outcomes included urinary albumin excretion rate (UAER), and the level of urinary albumin, ß2-microglobulin (ß2-MG), hypersensitive C-reactive protein (hs-CRP) and oxidative stress. RESULTS: 11 studies with 1294 participants were included in this study. The pooled analysis indicated that α-lipoic acid combined with valsartan could remarkably reduce UAER (P < 0.00001, SMD = -1.95, 95%CI = -2.55 to - 1.20; P = 0.03, SMD = -0.85, 95%CI = -1.59 to - 0.1) and the level of urinary albumin (P = 0.001, SMD = -1.48, 95%CI = - 2.38 to - 0.58; P = 0.01, SMD = -1.67, 95%CI = -3.00 to - 0.33), ß2-MG (P < 0.001,SMD = - 2.59, 95%CI = -3.78 to - 1.40; P = 0.03, SMD = -0.48, 95%CI = -0.93 to - 0.04) when compared with valsartan or lipoic acid monotherapy in patients with DN. However, there was no significant difference in the level of hs-CRP among the three therapies (P = 0.06, SMD = -2.80, 95%CI = -5.67 to 0.07; P = 0.10, SMD = -0.42, 95%CI = - 0.92 to 0.08). In addition, α-lipoic acid combined with valsartan markedly increased the level of SOD (P = 0.03, SMD = 1.24, 95%CI = 0.32 to 1.03; P = 0.0002, SMD = 0.68, 95%CI = 0.32 to 1.03) and T-AOC (P < 0.00001, SMD = 0.89, 95%CI = 0.62 to 1.16; P = 0.02, SMD = 0.58, 95%CI = 0.10 to1.07), and reduced the level of MDA(P = 0.0002, SMD = -1.99, 95%CI = -3.02 to - 0.96; P = 0.0001, SMD = -0.69, 95%CI = -1.04 to - 0.34). CONCLUSIONS: α-lipoic acid combined with valsartan could significantly reduce the level of urinary albumin and oxidative stress, increase antioxidant capacity and alleviate renal function damage in patients with DN, and this will provide a reference for the selection of treatment drugs for DN.

Investigation of an MAA Test With Virtual Sound Synthesis.

The ability to localize a sound source is very important in our daily life, specifically to analyze auditory scenes in complex acoustic environments. The concept of minimum audible angle (MAA), which is defined as the smallest detectable difference between the incident directions of two sound sources, has been widely used in the research fields of auditory perception to measure localization ability. Measuring MAAs usually involves a reference sound source and either a large number of loudspeakers or a movable sound source in order to reproduce sound sources at a large number of predefined incident directions. However, existing MAA test systems are often cumbersome because they require a large number of loudspeakers or a mechanical rail slide and thus are expensive and inconvenient to use. This study investigates a novel MAA test method using virtual sound source synthesis and avoiding the problems with traditional methods. We compare the perceptual localization acuity of sound sources in two experimental designs: using the virtual presentation and real sound sources. The virtual sound source is reproduced through a pair of loudspeakers weighted by vector-based amplitude panning (VBAP). Results show that the average measured MAA at 0° azimuth is 1.1° and the average measured MAA at 90° azimuth is 3.1° in a virtual acoustic system, meanwhile the average measured MAA at 0° azimuth is about 1.2° and the average measured MAA at 90° azimuth is 3.3° when using the real sound sources. The measurements of the two methods have no significant difference. We conclude that the proposed MAA test system is a suitable alternative to more complicated and expensive setups.

Adrenal Myelolipoma with Adrenocortical Adenoma Presenting with Hypertension Only.

Here, we present a case of a 25-year Chinese female who was diagnosed with non-functional adrenocortical adenoma containing myelolipoma with hypertension as the only symptom. Serum levels of cortisol, aldosterone, angiotensin I/II and renin activity were normal. Myelolipoma is a benign, non-functioning retroperitoneal tumour occurring predominantly in the adrenal gland and relatively uncommon. With the advancement of radiological studies, the incidental detection of myelolipoma has been noted. However, the coexistence of adrenal myelolipoma and adrenal adenoma still remains extremely rare. Though usually benign, the later may present with endocrine dysfunction, such as Cushing's syndrome, and requires proper management. Surgical resection is reserved for symptomatic tumours or large myelolipoma (>7 cm in size). The final diagnosis mainly relies on pathological examination. The left adrenal mass was completely removed via retroperitoneal laparoscopic approach. Postoperative recovery was uneventful and her blood pressure (BP) readings were normal. At 15 months follow-up, the patient was normotensive and there was no recurrence of tumour.

Shaping metal-organic framework materials with a honeycomb internal structure.

A self-assembly technology allows metal-organic framework materials to constitute a honeycomb internal structure while being shaped into millimeter-scale spheres. The ZIF-8 load is up to 83 wt% through solidification of chitosan (CS). This approach can be expanded to other morphologies (fibers) or crystals and is transformative for industrial manufacturing of nanomaterials.

Downregulation of SAFB Sustains the NF-κB Pathway by Targeting TAK1 during the Progression of Colorectal Cancer.

Purpose: To investigate the role and the underlying mechanism of scaffold attachment factor B (SAFB) in the progression of colorectal cancer (CRC).Experimental Design: SAFB expression was analyzed in the Cancer Outlier Profile Analysis of Oncomine and in 175 paraffin-embedded archived CRC tissues. Gene Ontology analyses were performed to explore the mechanism of SAFB in CRC progression. Western blot, RT-PCR, luciferase assay, and chromatin immunoprecipitation (ChIP) were used to detect the regulation of transforming growth factor-ß-activated kinase 1 (TAK1) and NF-κB signaling by SAFB The role of SAFB in invasion, metastasis, and angiogenesis was investigated using in vitro and in vivo assays. The relationship between SAFB and TAK1 was analyzed in CRC tissues.Results: SAFB was downregulated in CRC tissues, and low expression of SAFB was significantly associated with an aggressive phenotype and poorer survival of CRC patients. The downregulation of SAFB activated NF-κB signaling by targeting the TAK1 promoter. Ectopic expression of SAFB inhibited the development of aggressive features and metastasis of CRC cells both in vitro and in vivo The overexpression of TAK1 could rescue the aggressive features in SAFB-overexpressed cells. Furthermore, the expression of SAFB in CRC tissues was negatively correlated with the expression of TAK1- and NF-κB-related genes.Conclusions: Our results show that SAFB regulated the activity of NF-κB signaling in CRC by targeting TAK1 This novel mechanism provides a comprehensive understanding of both SAFB and the NF-κB signaling pathway in the progression of CRC and indicates that the SAFB-TAK1-NF-κB axis is a potential target for early therapeutic intervention in CRC progression. Clin Cancer Res; 23(22); 7108-18. ©2017 AACR.

MicroRNA-224 sustains Wnt/ß-catenin signaling and promotes aggressive phenotype of colorectal cancer.

BACKGROUND: Growing evidence suggests that Wnt/ß-catenin pathway plays an important role in CRC development, progression and metastasis. Aberrant miR-224 expression has been reported in CRC. However, the mechanism of miR-224 promotes both proliferation and metastatic ability largely remains unclear. METHODS: Real-time PCR was used to quantify miR-224 expression. Luciferase reporter assays were conducted to confirm the activity of Wnt/ß-catenin pathway and target gene associations, and immunofluorescence staining assay was performed to observe the nuclear translocation of ß-catenin. Bioinformatics analysis combined with in vivo and vitro functional assays showed the potential target genes, GSK3ß and SFRP2, of miR-224. Specimens from forty patients with CRC were analyzed for the expression of miR-224 and the relationship with GSK3ß/SFRP2 by real-time PCR and western blot. RESULTS: Bioinformatics and cell luciferase function studies verified the direct regulation of miR-224 on the 3'-UTR of the GSK3ß and SFRP2 genes, which leads to the activation of Wnt/ß-catenin signaling and the nuclear translocation of ß-catenin. In addition, knockdown of miR-224 significantly recovered the expression of GSK3ß and SFRP2 and attenuated Wnt/ß-catenin-mediated cell metastasis and proliferation. The ectopic upregulation of miR-224 dramatically inhibited the expression of GSK3ß/SFRP2 and enhanced CRC proliferation and invasion. CONCLUSION: Our research showed mechanistic links between miR-224 and Wnt/ß-catenin in the pathogenesis of CRC through modulation of GSK3ß and SFRP2.

TLE4 promotes colorectal cancer progression through activation of JNK/c-Jun signaling pathway.

The Groucho transcriptional co-repressor TLE4 protein has been shown to be a tumor suppressor in a subset of acute myeloid leukemia. However, little is known about its role in development and progression of solid tumor. In this study, we found that the expression of TLE4 in colorectal cancer (CRC) tissues was significantly higher than that in their matched adjacent intestine epithelial tissues. In addition, high expression of TLE4 was significantly correlated with advanced Dukes stage, lymph node metastasis and poor prognosis of CRC. Moreover, enforced expression of TLE4 in CRC cell lines significantly enhanced proliferation, invasion and tumor growth. On the contrary, knock down of TLE4 repressed cell proliferation, invasion and tumor growth. Furthermore, our study exhibited that the TLE4 promoted cell proliferation and invasion partially via activation of JNK-c-Jun pathway and subsequently increased cyclinD1 and decreased P27Kip1 expression. In conclusion, these results suggested that TLE4, a potential prognostic biomarker for CRC, plays an important role in the development and progression of human CRC.

The tumor-suppressor gene LZTS1 suppresses colorectal cancer proliferation through inhibition of the AKT-mTOR signaling pathway.

The Leucine zipper tumor suppressor gene 1 (LZTS1/FEZ1) gene was originally identified as a potential tumor suppressor. However, the expression pattern and the role of LZTS1 in the progression of colorectal cancer (CRC) have not been well characterized. Herein, we reported that LZTS1 was markedly reduced in CRC tissues compared with matched adjacent normal intestine epithelial tissues. In analysis of 160 CRC specimens, we revealed that decreased expression of LZTS1 was correlated to aggressive characteristics and poor survival of patients with CRC. Moreover, we found that expression of LZTS1 in CRC cells significantly inhibited cell proliferation in vitro and prohibited tumor growth in vitro. On the contrary, silence of LZTS1 promoted cell proliferation and tumor growth in CRC cells. Furthermore, we demonstrated that LZTS1 inhibited cell proliferation and tumor growth in CRC in part via suppression of AMT-mTOR, subsequently down-regulating p27Kip and up-regulating cyclin D1. These findings suggest that LZTS1 plays a potential tumor suppressor role in CRC progression and represents a valuable clinical prognostic marker of this disease.