Coffee and tea consumption and dementia risk: The role of sex and vascular comorbidities.

BACKGROUND: Coffee and tea consumption has been linked to dementia. However, it remained unknown how sex and vascular risk factors modify the association. We aimed to investigate the association of coffee and tea consumption with dementia and whether sex and vascular comorbidities modified the association. METHODS: We included 278 elderly patients with Alzheimer's disease (AD) and 102 patients with vascular dementia (VaD) from three hospitals; controls (N = 468) were recruited during the same period. We collected the frequency and amount of coffee and tea consumption and the presence of vascular comorbidities. The multinomial logistic regression model was utilized to evaluate the association of coffee and tea consumption with dementia, stratified by sex and vascular comorbidities. RESULTS: Different combinations and quantities of coffee and tea consumption protected against AD and VaD. Consumption of ≥3 cups of coffee or tea per day was protective against AD [adjusted odds ratio (aOR) = 0.42; 95% confidence interval (CI) = 0.22-0.78)] and VaD (aOR = 0.42; 95% CI = 0.19-0.94). Stratified analyses showed that the protective effects of a higher quantity of coffee and tea against AD were more pronounced among females and individuals with hypertension. Consumption of either coffee or tea was associated with a decreased risk of VaD among diabetic participants (aOR = 0.23; 95% CI = 0.06-0.98). Hyperlipidemia modified the association of coffee or tea consumption on the risk of AD and VaD (both Pinteraction < 0.01). CONCLUSION: The risk of AD and VaD was lower with increased consumption of coffee and tea; the impact differed by sex and vascular comorbidities including hypertension, hyperlipidemia, and diabetes.

Snail enhances arginine synthesis by inhibiting ubiquitination-mediated degradation of ASS1.

Snail is a dedicated transcriptional repressor and acts as a master inducer of EMT and metastasis, yet the underlying signaling cascades triggered by Snail still remain elusive. Here, we report that Snail promotes colorectal cancer (CRC) migration by preventing non-coding RNA LOC113230-mediated degradation of argininosuccinate synthase 1 (ASS1). LOC113230 is a novel Snail target gene, and Snail binds to the functional E-boxes within its proximal promoter to repress its expression in response to TGF-ß induction. Ectopic expression of LOC113230 potently suppresses CRC cell growth, migration, and lung metastasis in xenograft experiments. Mechanistically, LOC113230 acts as a scaffold to facilitate recruiting LRPPRC and the TRAF2 E3 ubiquitin ligase to ASS1, resulting in enhanced ubiquitination and degradation of ASS1 and decreased arginine synthesis. Moreover, elevated ASS1 expression is essential for CRC growth and migration. Collectively, these findings suggest that TGF-ß and Snail promote arginine synthesis via inhibiting LOC113230-mediated LRPPRC/TRAF2/ASS1 complex assembly and this complex can serve as potential target for the development of new therapeutic approaches to treat CRC.

Ajuba transactivates N-cadherin expression in colorectal cancer cells through interaction with Twist.

Ajuba is a multiple LIM domain-containing protein and functions as a transcriptional coregulator to modulate many gene expressions in various cellular processes. Here, we describe that the LIM domain of Ajuba interacts with Twist, and the Twist box is a pivotal motif for the interaction. Biologically, Ajuba enhances transcription of target gene N-cadherin as an obligate coactivator of Twist. The enhancement is achieved by binding to the E-box element within N-cadherin promoter as revealed by luciferase reporter and chromatin immunoprecipitation assays. Mechanistic investigation demonstrates that Ajuba recruits CBP and Twist to form a ternary complex at the Twist target promoter region and concomitantly enhances histone acetylation at these sites. These findings identify that Twist is a new interacting protein of Ajuba and Ajuba/Twist/CBP ternary complex may be a potential treatment strategy for Twist-related tumour metastasis.

Hypoxia facilitates the proliferation of colorectal cancer cells by inducing cancer-associated fibroblast-derived IL6.

Colorectal cancer (CRC) is the most common malignancy worldwide, and its underlying molecular mechanisms remain largely unexplored. Accumulating evidences indicate cancer-associated fibroblasts (CAFs), abundant stromal cell population in the tumor microenvironment, play a key role in tumor development. Herein, we have successfully isolated CAFs and paired normal fibroblasts (NFs) from colorectal cancer tissues (n=10). By using a multiplex cytokine profiling assay, we have identified IL-6 as a major cytokine released by CAFs. Co-culturing of CAFs with CRC cell lines HCT116 or SW480 increases IL-6 release, and the secretion by CAFs can be further enhanced under hypoxia. By using the CCK-8 assay, we have found that HCT116 or SW480 cells treated with culture medium from CAFs, IL-6, or hypoxia showed a significant cell growth compared to control cells (p<0.01). Mechanistically, we have found that hypoxia could enhance the effect of the IL-6/STAT3 signaling on CRC cells, in part, through HIF-1a targeting PKM2. In conclusion, our data clearly proposes the interconnected mechanisms for constitutive activation of STAT3 signal by CAFs-derived IL-6 under hypoxia in colorectal cancer. The pharmacological inhibition of STAT3, PKM2, or HIF-1α can significantly reduce the oncogenic effect of IL-6, providing a potential therapeutic target for CRC patients.

Inhibiting miR-21 attenuates experimental hepatic fibrosis by suppressing both the ERK1 pathway in HSC and hepatocyte EMT.

MicroRNA-21 (miR-21) has emerged as a critical regulatory molecule and an important serum marker in hepatic fibrogenesis. The aim of the present study was to investigate the role of inhibiting miR-21 on hepatic fibrosis treatment. Serum miR-21 levels in 60 healthy individuals and 180 patients with different stages of liver cirrhosis were examined, miR-21 levels in normal or cirrhotic human liver tissues (n=10 each) were also detected. An adenoviral vector (Ad-TuD-21) carrying the sponging ToughDecoy (TuD)-RNA sequence against miR-21 was constructed to reduce miR-21 expression efficiently in vitro and in vivo Histological and immunohistological examinations were performed to evaluate the inhibitory effects and mechanism of Ad-TuD-21 delivery into carbon tetrachloride (CCl4) induced hepatic fibrosis rats by targeting extracellular signal-regulated kinase 1 (ERK1) signalling in hepatic stellate cells (HSC) and hepatocyte epithelial-mesenchymal transition (EMT). Our results revealed that enhanced miR-21 levels in cirrhotic patients were related to the severity and activity of liver cirrhosis. Ad-TuD-21 administered to liver fibrosis rats could remarkably suppress profibrotic gene expression, cause histological improvements in liver and attenuate hepatic fibrosis significantly. More importantly, after Ad-TuD-21 treatment, inhibition of both the ERK1 signalling pathway in HSC and hepatocyte EMT was confirmed, which paralleled the enhancement of miR-21 target genes-sprouty2 (SPRY2) and hepatocyte nuclear factor 4α (HNF4α)-expression in vivo These data demonstrated that miR-21 is a key regulator to promote hepatic fibrogenesis, and sponging miR-21 expression may present a novel potentially therapeutic option for hepatic fibrosis.

Genetic polymorphisms of lipid metabolism gene SAR1 homolog B and the risk of Alzheimer's disease and vascular dementia.

BACKGROUND/PURPOSE: Lipid metabolism is involved in beta amyloid generation, which has been related with the progression of Alzheimer's disease (AD). No study has explored the association between polymorphisms of SAR1 homolog B (SAR1B) and the risk of dementia previously. METHODS: This is a case-control study. A total of 279 AD and 117 vascular dementia (VaD) patients were recruited from neurology clinics at three teaching hospitals in Taiwan from 2007 to 2010. Controls (n = 466) were recruited from the elderly health checkup program and volunteers in the hospital during the same time interval. Three common (frequency ≥ 5%) haplotype-tagging single nucleotide polymorphisms were selected from the lipid metabolism gene SAR1B to assess its association with AD and VaD. RESULTS: Homozygous variants of rs11948613 were associated with a decreased AD risk (CC vs. TT: adjusted odds ratio = 0.39, 95% confidence interval = 0.15-0.98) with a population attributable risk of 26.7%. This association decreased further in apolipoprotein E ε4 (ApoE ε4) noncarriers (adjusted odds ratio = 0.28, 95% confidence interval = 0.09-0.91). No association was found for VaD. Two common haplotypes (with a cumulative frequency of 95.7% in controls) were identified for SAR1B, and no association was found for AD or VaD. Simultaneous screening using rs11948613 and ApoE ε4 significantly improved the sensitivity of ApoE ε4 alone (from 0.40 to 0.75). CONCLUSION: SAR1B polymorphisms were associated with AD risk; results were not significant after correction for multiple tests. Simultaneous screening using SAR1B rs11948613 and ApoE ε4 status offered a better sensitivity for AD screening.

Sequence variants of the aging gene CISD2 and the risk for Alzheimer's disease.

BACKGROUND/PURPOSE: The CISD2 gene has been related to life span control and mitochondrial dysfunction in animals. In addition, inhibition of mitochondrial enzymes due to an accumulation of beta-amyloid peptide has been related to Alzheimer's disease (AD). This study aimed to explore the association between sequence variants of the CISD2 gene and risk for AD, which has not been explored previously. METHODS: This was a case-control study involving a total of 276 patients with AD who were recruited from three teaching hospitals in Taiwan from 2007 to 2010; 460 controls were recruited from elderly individuals attending for health check-ups and volunteers in the hospital during the same period of time. All participants were aged 60 years or older. Two haplotype-tagging single nucleotide polymorphisms (htSNPs), rs223330 and rs223331, were selected from the CISD2 gene to test the association between their polymorphisms and the risk for dementia, and how ApoE ɛ4 status, sex, hypertension, and type 2 diabetes mellitus might modify this association. RESULTS: rs223330 variant carriage was not associated with risk for AD [TT versus CC: adjusted odds ratio (AOR) = 0.98, 95% confidence interval (CI) = 0.59-1.62; TC versus CC: AOR = 0.72, 95% CI = 0.47-1.11]. Similar findings were observed for rs223331 (AA versus TT: AOR = 1.12; AT versus TT: AOR = 0.99). In addition, hypertension significantly modified the association between rs223331 and risk for AD (p = 0.005).Three common haplotypes (with a frequency of 99.8%) were observed for CISD2. Common CISD2 haplotypes were not associated with the risk for AD. CONCLUSION: Our findings suggested that CISD2 htSNPs are not associated with AD risk.

Leisure activities, apolipoprotein E e4 status, and the risk of dementia.

BACKGROUND/PURPOSE: Leisure activities have been associated with a decreased risk of dementia. However, to date, no study has explored how apolipoprotein E (ApoE) e4 status or vascular risk factors modified the association between leisure activities and dementia risks. METHODS: This case-control study recruited patients (age ≥ 60 years) with Alzheimer's disease (AD; n = 292) and vascular dementia (VaD; n = 144) and healthy controls (n = 506) from three teaching hospitals in Taiwan between 2007 and 2010. Information on patient's leisure activities were obtained through a questionnaire. Conditional logistic regression models were used to assess the association of leisure activities and ApoE e4 status with the risk of dementia. RESULTS: High-frequency physical activity was associated with a decreased risk of AD [adjusted odds ratio (AOR) = 0.45], and the results become more evident among ApoE e4 carriers with AD (AOR = 0.30) and VaD (AOR = 0.26). Similar findings were observed for cognitive (AOR = 0.42) and social activities (AOR = 0.55) for AD. High-frequency physical, cognitive, and social activities were associated with a decreased risk of VaD (AOR = 0.29-0.60). Physical and social activities significantly interacted with each other on the risk of VaD (pinteraction = 0.04). CONCLUSION: Physical activity consistently protects against AD and VaD. Significant interactions were identified across different types of leisure activities in lowering dementia risk.

WDR68 stimulates cellular proliferation via activating ribosome biogenesis in 293T cells.

WDR68, a conserved WD40 repeat-containing protein, interacts with E1A and is involved in the E1A-induced cell proliferation and oncogenic transformation, but the intrinsic molecular mechanisms of this process remain to be elucidated. Here, we demonstrate that WDR68 promotes the proliferation of 293T cells by interacting with a series of ribosome biogenesis-regulating proteins. Gene Set Enrichment Analysis (GSEA) of RNA-seq data also revealed that the ribosome biogenesis-associated gene signatures could be the most significantly enriched in the WDR68 expression groups. In accordance, 293T cells are more sensitive to the ribosome biogenesis inhibitors than 293 cells. Taken together, our results indicated that WDR68 could promote cell proliferation through the activation of ribosome biogenesis in the 293T cell context. This provides new insights into the understanding of the function of WDR68 and the molecular characterisation of 293T tool cells.

Improved dual-aggregation polyp segmentation network combining a pyramid vision transformer with a fully convolutional network.

Automatic and precise polyp segmentation in colonoscopy images is highly valuable for diagnosis at an early stage and surgery of colorectal cancer. Nevertheless, it still posed a major challenge due to variations in the size and intricate morphological characteristics of polyps coupled with the indistinct demarcation between polyps and mucosas. To alleviate these challenges, we proposed an improved dual-aggregation polyp segmentation network, dubbed Dua-PSNet, for automatic and accurate full-size polyp prediction by combining both the transformer branch and a fully convolutional network (FCN) branch in a parallel style. Concretely, in the transformer branch, we adopted the B3 variant of pyramid vision transformer v2 (PVTv2-B3) as an image encoder for capturing multi-scale global features and modeling long-distant interdependencies between them whilst designing an innovative multi-stage feature aggregation decoder (MFAD) to highlight critical local feature details and effectively integrate them into global features. In the decoder, the adaptive feature aggregation (AFA) block was constructed for fusing high-level feature representations of different scales generated by the PVTv2-B3 encoder in a stepwise adaptive manner for refining global semantic information, while the ResidualBlock module was devised to mine detailed boundary cues disguised in low-level features. With the assistance of the selective global-to-local fusion head (SGLFH) module, the resulting boundary details were aggregated selectively with these global semantic features, strengthening these hierarchical features to cope with scale variations of polyps. The FCN branch embedded in the designed ResidualBlock module was used to encourage extraction of highly merged fine features to match the outputs of the Transformer branch into full-size segmentation maps. In this way, both branches were reciprocally influenced and complemented to enhance the discrimination capability of polyp features and enable a more accurate prediction of a full-size segmentation map. Extensive experiments on five challenging polyp segmentation benchmarks demonstrated that the proposed Dua-PSNet owned powerful learning and generalization ability and advanced the state-of-the-art segmentation performance among existing cutting-edge methods. These excellent results showed our Dua-PSNet had great potential to be a promising solution for practical polyp segmentation tasks in which wide variations of data typically occurred.

Association of pro-inflammatory diet with increased risk of gallstone disease: a cross-sectional study of NHANES January 2017-March 2020.

Background and aim: Gallstone disease (GSD) is a major public health problem worldwide. The dietary inflammatory index (DII) and the energy-adjusted DII (E-DII) have been used to describe dietary inflammatory potential. The current study sought to investigate the pro-inflammatory role of diet on GSD among outpatients in the United States. Methods: Cross-sectional data from 7,334 individuals older than 20 years who participated in the National Health and Nutrition Examination Survey (NHANES) from January 2017 to March 2020 were obtained. The relationship between GSD and DII was assessed using self-reported data. An association between DII and the risk of GSD was determined using sample-weighted logistic regression and restricted cubic splines (RCS). Subgroup analyzes were conducted to assess the interaction between DII and related factors. Sensitivity analysis was further used to confirm the stability of the relationship. To control for the effect of total energy intake, E-DII was calculated and analyzed. Results: A total of 10.5% of the study participants had GSD. The DII ranged from -5.52 to 5.51, and the median DII was significantly higher for participants with GSD than those without (1.68 vs. 1.23, p < 0.001). There was a significant and stable positive relationship between DII and GSD in adjusted models (OR 1.10, 95% CI 1.00-1.20). In the fully adjusted model, subjects with DII scores in the highest tertile were more likely to have GSD than those in the lowest tertile (OR 1.52, 95% CI 1.19-1.93). An apparent dose-response association between DII and GSD was detected. The association between E-DII and GSD remained stable. Conclusion: Higher DII/E-DII scores linked to the intake of a pro-inflammatory diet were positively associated with a higher risk of GSD. These findings suggest that pro-inflammatory dietary patterns can promote the formation of gallstones.

GATA zinc finger protein p66ß promotes breast cancer cell migration by acting as a co-activator of Snail.

The transcriptional repressor Snail induces EMT during embryonic development and tumor metastasis. Growing evidence indicates that Snail functions as a trans-activator to induce gene expression; however, the underlying mechanism remains elusive. Here, we report that Snail cooperates with GATA zinc finger protein p66ß to transactivate genes in breast cancer cells. Biologically, depletion of p66ß reduces cell migration and lung metastasis in BALB/c mice. Mechanistically, Snail interacts with p66ß and cooperatively induces gene transcription. Notably, a group of genes induced by Snail harbor conserved G-rich cis-elements (5'-GGGAGG-3', designated as G-box) in their proximal promoter regions. Snail directly binds to G-box via its zinc fingers and transactivates the G-box-containing promoters. p66ß enhances Snail binding affinity to G-box, whereas depletion of p66ß results in a decreased binding affinity of Snail to the endogenous promoters and concomitantly reduces the transcription of Snail-induced genes. Taken together, these data demonstrated that p66ß is critical for Snail-mediated cell migration by acting as a co-activator of Snail to induce genes containing G-box elements in the promoters.

Sequence variants of interleukin 6 (IL-6) are significantly associated with a decreased risk of late-onset Alzheimer's disease.

BACKGROUND: Interleukin 6 (IL-6) has been related to beta-amyloid aggregation and the appearance of hyperphosphorylated tau in Alzheimer's disease (AD) brain. However, previous studies relating IL-6 genetic polymorphisms to AD included few and unrepresentative single nucleotide polymorphisms (SNPs) and the results were inconsistent. METHODS: This is a case-control study. A total of 266 patients with AD, aged≧65, were recruited from three hospitals in Taiwan (2007-2010). Controls (n = 444) were recruited from routine health checkups and volunteers of the hospital during the same period of time. Three common IL-6 haplotype-tagging SNPs were selected to assess the association between IL-6 polymorphisms and the risk of late-onset AD (LOAD). RESULTS: Variant carriers of IL-6 rs1800796 and rs1524107 were significantly associated with a reduced risk of LOAD [(GG + GC vs. CC): adjusted odds ratio (AOR) = 0.64 and (CC + CT vs. TT): AOR = 0.60, respectively]. Haplotype CAT was associated with a decreased risk of LOAD (0 and 1 copy vs. 2 copies: AOR = 0.65, 95% CI = 0.44-0.95). These associations remained significant in ApoE e4 non-carriers only. Hypertension significantly modified the association between rs2069837 polymorphisms and the risk of LOAD (pinteraction = 0.03). CONCLUSIONS: IL-6 polymorphisms are associated with reduced risk of LOAD, especially in ApoE e4 non-carriers. This study identified genetic markers for predicting LOAD in ApoE e4 non-carriers.

Genetic polymorphisms of nerve growth factor receptor (NGFR) and the risk of Alzheimer's disease.

BACKGROUND: Loss of basal forebrain cholinergic neurons is attributable to the proapoptotic signaling induced by nerve growth factor receptor (NGFR) and may link to Alzheimer's disease (AD) risk. Only one study has investigated the association between NGFR polymorphisms and the risk of AD in an Italian population. Type 2 diabetes mellitus (DM) may modify this association based on previous animal and epidemiologic studies. METHODS: This was a case-control study in a Chinese population. A total of 264 AD patients were recruited from three teaching hospitals between 2007 to 2010; 389 controls were recruited from elderly health checkup and volunteers of the hospital during the same period of time. Five common (frequency≥5%) haplotype-tagging single nucleotide polymorphisms (htSNPs) were selected from NGFR to test the association between NGFR htSNPs and the risk of AD. RESULTS: Variant NGFR rs734194 was significantly associated with a decreased risk of AD [GG vs. TT copies: adjusted odds ratio (OR) = 0.43, 95% confidence interval (CI) = 0.20-0.95]. Seven common haplotypes were identified. Minor haplotype GCGCG was significantly associated with a decreased risk of AD (2 vs. 0 copies: adjusted OR = 0.39, 95% CI = 0.17-0.91). Type 2 DM significantly modified the association between rs2072446, rs741072, and haplotype GCTTG and GTTCG on the risk of AD among ApoE ε4 non-carriers (P(interaction) < 0.05). CONCLUSION: Inherited polymorphisms of NGFR were associated with the risk of AD; results were not significant after correction for multiple tests. This association was further modified by the status of type 2 DM.

The prognostic value and immunological role of angiogenesis-related patterns in colon adenocarcinoma.

Colon adenocarcinoma (COAD) is a malignant tumor with a high mortality rate. Angiogenesis plays a key role in the development and progression of cancer. However, in COAD, studies between angiogenesis and prognosis, immune cell infiltration, and personalized treatment guidance are currently lacking. In the present study, we comprehensively assessed 35 angiogenesis-related genes (ARG) and identified key ARGs affecting OS in COAD patients. The ARG Prognostic Index (ARGPI) was constructed based on a univariate Cox regression model and its prognostic value was evaluated in TCGA-COAD, GSE39582, GSE161158 and TRSJTUSM Cohort. We constructed ARGPI as an independent risk factor for OS in COAD patients and combined with clinical parameters to further construct an ARGPI-based nomogram, which showed a strong ability to predict overall survival in COAD patients. High ARGPI is associated with cancer-related and immune-related biological processes and signaling pathways; high TP53 mutation rate; high infiltration of MSC, pericytes, and stromal cells; and more CMS4 subtype. And low ARGPI benefited more from immune checkpoint inhibitor treatment. In addition, we also predicted the sensitivity of different ARGPI groups to common chemotherapeutic and targeted agents. In conclusion, this study constructed an ARGPI based on ARG, which robustly predicted the OS of COAD patients and provided a possible personalized treatment regime for COAD patients.

Swimming Impedes Intestinal Microbiota and Lipid Metabolites of Tumorigenesis in Colitis-Associated Cancer.

Background: Accumulating data support that regular physical activity potentially inhibits chronic colitis, a risk factor for colitis-associated cancer (CAC). However, possible effects of physical activity on CAC and the underlying mechanisms remain poorly understood. Methods: A pretreatment of swimming on azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CAC mice was implemented to determine its protective effect. Inflammation and tumorigenesis were assessed using colorectums from C57BL/6 mice. In order to determine how swimming alters colonic lipid metabolism and gene expression, a comparative analysis was conducted. Meanwhile, alterations in intestinal microbiota and short-chain fatty acids (SCFAs) were detected and analyzed. Finally, an integration analysis of colonic lipid metabolism with gene expression and intestinal microbiota was performed respectively. Result: Swimming pretreatment relieved bowel inflammation and minimized tumor formation. We demonstrated that prostaglandin E2 (PGE2)/PGE2 receptor 2 subtype (EP2) signaling as a potential regulatory target for swimming induces colonic lipid metabolites. Swimming-induced genera, Erysipelatoclostridium, Parabacteroides, Bacteroides, and Rikenellaceae_RC9_gut_group, induced intestinal SCFAs and affected the function of colonic lipid metabolites enriched in glycerophospholipid metabolism and choline metabolism in cancer. Conclusion: According to our experiments, swimming pretreatment can protect mice from CAC by intervention in the possible link between colonic lipid metabolites and PGE2/EP2 signaling. Further, swimming-induced genera and probiotics promoted glycerophospholipid metabolism and choline metabolism in cancer, the major constituents of colonic lipid metabolites, and increased SCFAs, which were also important mechanisms for the anti-inflammatory and anti-tumorigenic effects of swimming.

Analysis of transcript-wide profile regulated by microsatellite instability of colorectal cancer.

Background: Microsatellite instability-high (MSI-H) is a form of genomic instability present in 15% of colorectal cancer (CRC) cases. Several differential gene analyses have been conducted on CRC; however, none have specifically explored the differentially expressed genes in MSI-H CRC. Research on the different gene expressions between MSI-H CRC and microsatellite stable (MSS) CRC, and their different patterns of metastasis will provide invaluable insights for diagnosis, prognosis, and treatment. Methods: In this study, the differential expression of 46,602 genes were analyzed across 613 different tissue samples from The Cancer Genome Atlas (TCGA)-colon adenocarcinoma (COAD) and TCGA-rectum adenocarcinoma (READ) as part of a gene association analysis. R package TCGAbiolinks (version 2.18.0) was used to download the data set, and DESeq2 (version 1.30.1) was used for the differential gene analysis. The resulting genes were then analyzed for shared pathways with R package clusterProfiler (version 3.0.4). Results: A total of 237 significantly differentially expressed genes (Padj<0.05) were found between MSI-H and MSS CRC. Differentially expressed genes include insulin like growth factor 2 (IGF2) and fibroblast growth factor 3 (FGF3), and the enriched pathways mostly involve hearing, digestive regulation, and neurogenesis.463 differentially expressed genes were found between metastatic and non-metastatic CRC. Notably differentially expressed genes in metastatic CRC include DEAD-box helicase 53 (DDX53) and adiponectin, C1Q and collagen domain containing (ADIPOQ), and enriched pathways include the immune system, cell adhesion, and cell signaling. For MSI-H CRC, a total of 34 genes were significantly differently expressed between metastatic and non-metastatic CRC. These include notum, palmitoleoyl-protein carboxylesterase (NOTUM), serpin family B member 2 (SERPINB2), and several keratin (KRT) genes, and the pathway analysis showed the major enrichment of the hormonal and secretion and regulation pathways. Of the differentially expressed genes in metastatic CRC, 25 were immunity related and include fatty acid binding protein 4 (FABP4), and the pathway analysis showed the enrichment of humoral immunity and lymphocyte regulation. Conclusions: Of the biologically plausible differentially expressed genes, the most notable were NOTUM, KRT6A, KRT14, SERPINB2, and serum amyloid A1 (SAA1). NOTUM, KRT6A, and KRT14 are active in the Wnt pathway. All five are also involved in various inflammation pathways.

DLC1 inhibits colon adenocarcinoma cell migration by promoting secretion of the neurotrophic factor MANF.

DLC1 (deleted in liver cancer-1) is downregulated or deleted in colorectal cancer (CRC) tissues and functions as a potent tumor suppressor, but the underlying molecular mechanism remains elusive. We found that the conditioned medium (CM) collected from DLC1-overexpressed SW1116 cells inhibited the migration of colon adenocarcinoma cells HCT116 and SW1116, but had no effect on proliferation, which suggested DLC1-mediated secretory components containing a specific inhibitor for colon adenocarcinoma cell migration. Analysis by mass spectrometry identified mesencephalic astrocyte-derived neurotrophic factor (MANF) as a candidate. More importantly, exogenous MANF significantly inhibited the migration of colon adenocarcinoma cells HCT116 and SW1116, but did not affect proliferation. Mechanistically, DLC1 reduced the retention of MANF in ER by competing the interaction between MANF and GRP78. Taken together, these data provided new insights into the suppressive effects of DLC1 on CRC, and revealed the potential of MANF in the treatment of CRC.

The anti-tumor effects of the combination of microwave hyperthermia and lobaplatin against breast cancer cells in vitro and in vivo.

BACKGROUND: Breast cancer is the main lethal disease among females. The combination of lobaplatin and microwave hyperthermia plays a crucial role in several kinds of cancer in the clinic, but its possible mechanism in breast cancer has remained indistinct. METHODS: Mouse models were used to detect breast cancer progression. Cell growth was explored with MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphonyl)-2H-tetrazolium) and colony formation assays. Cell migration and invasion were investigated with a transwell assay. Cell apoptosis was probed with flow cytometry. The expression of apoptosis-associated proteins was examined with Western blots. RESULT: Combination treatment decreased breast cancer cell viability, colony formation, cell invasion and metastasis. In addition, the treatment-induced breast cancer cell apoptosis and autophagy, activated the c-Jun N-terminal kinase (JNK) signaling pathway, suppressed the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, and down-regulated IAP and Bcl-2 family protein expression. CONCLUSION: These results indicate that lobaplatin is an effective breast cancer anti-tumor agent. Microwave hyperthermia was a useful adjunctive treatment. Combination treatment was more efficient than any single therapy. The possible mechanism for this effect was mainly associated with activation of the JNK signaling pathway, inactivation of the AKT/mTOR signaling pathway and down-regulation of the Bcl-2 and IAP families.

A KLF4/PiHL/EZH2/HMGA2 regulatory axis and its function in promoting oxaliplatin-resistance of colorectal cancer.

Long noncoding RNAs (lncRNAs) have emerged as a new class of regulatory molecules implicated in therapeutic resistance, yet the mechanisms underlying lncRNA-mediated oxaliplatin resistance in colorectal cancer (CRC) are poorly understood. In this study, lncRNA P53 inHibiting LncRNA (PiHL) was shown to be highly induced in oxaliplatin-resistant CRC cells and tumor tissues. In vitro and in vivo models clarified PiHL's role in conferring resistance to oxaliplatin-induced apoptosis. PiHL antagonized chemosensitivity through binding with EZH2, repressing location of EZH2 to HMGA2 promoter, and downregulating methylation of histone H3 lysine 27 (H3K27me3) level in HMGA2 promoter, thus activating HMGA2 expression. Furthermore, HMGA2 upregulation induced by PiHL promotes PI3K/Akt phosphorylation, which resulted in increased oxaliplatin resistance. We also found that transcription factor KLF4 was downregulated in oxaliplatin-resistant cells, and KLF4 negatively regulated PiHL expression by binding to PiHL promoter. In vivo models further demonstrated that treatment of oxaliplatin-resistant CRC with locked nucleic acids targeting PiHL restored oxaliplatin response. Collectively, this study established lncRNA PiHL as a chemoresistance promoter in CRC, and targeting PiHL/EZH2/HMGA2/PI3K/Akt signaling axis represents a novel choice in the investigation of drug resistance.