The overexpression of SOX4 in various kinds of cancer cells was associated with poor prognosis for patients. The role of SOX4 in angiogenesis and tumor microenvironment modulation was recently ...documented in breast cancer but remains unclear in hepatocellular carcinoma (HCC). In our study, the clinical relevance of SOX4 overexpression in HCC and its role in the tumor microenvironment were investigated. The overexpression of SOX4 (SOX4
) in tumor lesions was associated with higher microvessel density (P = 0.012), tumor thrombosis formation (P = 0.012), distant metastasis (P < 0.001), and an independent prognostic factor for disease-free survival in HCC patients (P = 0.048). Endogenous SOX4 knockout in Hep3B cells by the CRISPR/cas9 system reduced the expression of CXCL12, which, in turn, attenuated chemotaxis in human umbilical vein endothelial cells, tube formation in vitro, reduced tumor growth, reticular fiber production, and angiogenesis in vivo in a xenograft mouse model. Treatment with an antagonist targeting CXCR4 (AMD3100), a receptor of CXCL12, inhibited chemotaxis and tube formation in endothelial cells in vitro. The CXCL12 promoter was activated by ectopic expression of a Flag-tagged SOX4 plasmid, endogenous SOX4 knockdown abolished promoter activity of CXCL12 as shown by luciferase assays, and an association with the CXCL12 promoter was identified via chromatin immunoprecipitation in HCC cells. In conclusion, SOX4 modulates the CXCL12 promoter in HCC cells. The secretory CXCL12, in turn, modulates CXCR4 in endothelial cells, reticular fibers to regulate the tumor microenvironment and modulate neovascularization, which might contribute to the distant metastasis of tumors.
Approximately 45% of metastatic colorectal cancer (mCRC) patients with wild-type KRAS exon 2 are resistant to cetuximab treatment. We set out to identify additional genetic markers that might predict ...the response to cetuximab treatment. Fifty-three wild-type KRAS exon 2 mCRC patients were treated with cetuximab/irinotecan-based chemotherapy as a first- or third-line therapy. The mutational statuses of 10 EGFR pathway genes were analyzed in primary tumors using next-generation sequencing. BRAF, PIK3CA, KRAS (exons 3 and 4), NRAS, PTEN, and AKT1 mutations were detected in 6, 6, 5, 4, 1, and 1 patient, respectively. Four of the BRAF mutations were non-V600 variants. Four tumors harbored multiple co-existing (complex) mutations. All patients with BRAF mutations or complex mutation patterns were cetuximab non-responders. All patients but one harboring KRAS, NRAS, or BRAF mutations were non-responders. Mutations in any one of these three genes were associated with a poor response rate (7.1%) and reduced survival (PFS = 8.0 months) compared to wild-type patients (74.4% and 11.6 months). Our data suggest that KRAS, NRAS, and BRAF mutations predict response to cetuximab treatment in mCRC patients.
Epidermal growth factor receptor (EGFR) and activin A are both overexpressed in oral cavity squamous cell carcinoma (OSCC). We evaluated their clinical correlation and activin A-mediated EGFR ...regulation in this study. Overexpression of both transcripts/proteins indicated a poorer prognosis in OSCC patients. Knockdown of endogenous INHBA repressed the expression of EGFR and inhibited activin A-mediated canonical Smads, noncanonical phosphorylation of AKT (ser473) (p-AKT ser473) and SP1. Inhibition of PI3K signaling via its inhibitor attenuated p-AKT ser473 and in turn reduced SP1 and EGFR expression in the presence of recombinant activin A (rActivin A) in OSCC cells, as revealed via a luciferase assay and western blotting. However, canonical Smad signaling repressed the EGFR promoter, as revealed by a luciferase assay. The transcription factor SP1, its coactivator CBP/p300, and Smad proteins were recruited to the EGFR proximal promoter following rActivin A treatment, as revealed by chromatin immunoprecipitation (ChIP). Smad2/3/4 dramatically outcompeted SP1 binding to the EGFR proximal promoter following mithramycin A treatment. Activin A activates the PI3K and Smad pathways to compete for binding to overlapping SP1 consensus sequences on the EGFR proximal promoter. Nevertheless, canonical p-Smad2 was largely repressed in OSCC tumor tissues, suggesting that the activin A-mediated noncanonical pathway is essential for the carcinogenesis of OSCC.
Glucagon-like peptide-1 receptor agonist (GLP-1 RA) is probably one of more effective antidiabetic agents in treatment of type 2 diabetes mellitus (T2D). However, the heterogenicity in responses to ...GLP-1 RA may be potentially related to gut microbiota, although no human evidence has been published. This pilot study aims to identify microbial signatures associated with glycemic responses to GLP-1 RA.
Microbial compositions of 52 patients with T2D receiving GLP-1 RA were determined by 16S rRNA amplicon sequencing. Bacterial biodiversity was compared between responders versus non-responders. Pearson's correlation and random forest tree algorithm were used to identify microbial features of glycemic responses in T2D patients and multivariable linear regression models were used to validate clinical relevance.
Beta diversity significantly differed between GLP-1 RA responders (
= 34) and non-responders (
= 18) (ADONIS,
= 0.004). The top 17 features associated with glycohemoglobin reduction had a 0.96 diagnostic ability, based on area under the ROC curve:
and
, the two microbes having immunomodulation effects, along with
sp. and
sp., were positively correlated with glycemic reduction;
, the microbe related to insulin resistance, together with
sp., Bacteroidales sp.,
sp.,
,
,
spp.,
,
sp., and
had negative correlation. Furthermore,
,
sp. and
were significant after adjusting for baseline glycohemoglobin and C-peptide concentrations, two clinical confounders.
Unique gut microbial signatures are associated with glycemic responses to GLP-RA treatment and reflect degrees of dysbiosis in T2D patients.
Stress-induced phosphoprotein-1 (STIP1)-a heat shock protein (HSP)70/HSP90 adaptor protein-is commonly overexpressed in malignant cells, where it controls proliferation via multiple signaling ...pathways, including JAK2/STAT3. We have previously shown that STIP1 stabilizes the protein tyrosine kinase JAK2 in cancer cells via HSP90 binding. In this study, we demonstrate that STIP1 may act as a substrate for JAK2 and that phosphorylation of tyrosine residues 134 and 152 promoted STIP1 protein stability, induced its nuclear-cytoplasmic shuttling, and promoted its secretion into the extracellular space. We also found that JAK2-mediated STIP1 phosphorylation enhanced cell viability and increased resistance to cisplatin-induced cell death. Conversely, interference STIP1 with JAK2 interaction-attained either through site-directed mutagenesis or the use of cell-penetrating peptides-decreased JAK2 protein levels, ultimately leading to cell death. On analyzing human ovarian cancer specimens, JAK2 and STIP1 expression levels were found to be positively correlated with each other. Collectively, these results indicate that JAK2-mediated phosphorylation of STIP-1 is critical for sustaining the JAK2/STAT3 signaling pathway in cancer cells.
The miRNA participates in a variety of biologic processes, and dysregulation of miRNA is associated with malignant transformation. In this study, we determined specific profile of miRNA associated ...with oral cancer by using miRNA array screening method. There were 23 miRNAs found with considerably differential expressions between six oral cancer cell lines and five lines of normal oral keratinocytes, in which, 10 miRNAs showed the highest significant difference after independent examination by reverse transcription quantitative PCR. Eight molecules were upregulated, miR-10b, miR-196a, miR-196b, miR-582-5p, miR-15b, miR-301, miR-148b, and miR-128a, and two molecules, miR-503 and miR-31, were downregulated. The most upregulated miR-10b was further examined, and its functions were characterized in two oral cancer cell lines. The miR-10b actively promotes cell migration (2.6- to 3.6-fold) and invasion (1.7- to 1.9-fold) but has minimal effect on cell growth or chemo-/radiosensitivity. Furthermore, miR-10b was considerably elevated in the plasma of xenografted tumor mice (20-fold). This upregulation of miR-10b in plasma was further shown in the patients with oral cancer P < 0.0001, area under curve (AUC) = 0.932 and precancer lesions (P < 0.0001, AUC = 0.967), suggesting that miR-10b possesses a high potential to discriminate the normal subjects. In conclusion, we have identified at least 10 miRNAs significantly associated with oral cancer, including the most elevated miR-10b. The miR-10b actively participates in cancer formation by promoting cell migration and invasion. Our study using clinical samples suggests that plasma miR-10b has high potential as an early detection marker for oral cancer.
Background. Norovirus and rotavirus cause outbreaks of diarrheal disease worldwide. This prospective observational study was undertaken to investigate the clinical characteristics and complications, ...with a focus on convulsive disorders, of gastroenteritis caused by norovirus and rotavirus in hospitalized pediatric patients in northern Taiwan. Methods. Children hospitalized with acute gastroenteritis in Chang Gung Children's Hospital from August 2004 through January 2007 were enrolled in the study. Rotavirus and norovirus were detected by reverse-transcriptase polymerase chain reaction with fecal specimens and were genotyped by sequence analysis. The symptoms and complications, in particular convulsions, of acute gastroenteritis caused by rotavirus and norovirus were reviewed and compared. The occurrence of convulsions associated with norovirus infection was specifically analyzed and discussed. The neurological outcomes for all norovirus-infected patients with or without convulsions were followed up for 1 year. Results. Among the 353 patients with acute viral gastroenteritis without coinfection, rotavirus and norovirus isolates were detected in 101 patients (28.6%) and 64 patients (18.1%), respectively. We compared the symptoms between the 2 groups and found that rotavirus caused a higher frequency and longer duration of vomiting and a higher body temperature than did norovirus. Norovirus infection, on the other hand, caused significantly longer hospital stays (mean duration of stay interquartile range, 6 5–8 days vs. 5 4–7 days; P<.001) and a significantly higher incidence of convulsions than did rotavirus infection (29.7% vs. 5%; P<.001). Three of the 19 patients with convulsions showed an abnormal record on electroencephalogram, but none had any neurological sequelae at the subsequent 1-year follow-up. The majority of norovirus strains (41 of the 56 genotypeable strains) belonged to genogroup GGII/4. Conclusions. Norovirus is a major cause of acute gastroenteritis in children. This study identified norovirus as an emerging agent causing convulsive disorder in children, particularly in young infants. Long-term neurological sequelae are uncommon.
Esculetin, a coumarin derivative from various natural plants, has an anti-inflammatory property. In the present study, we examined if esculetin has any salutary effects against lipopolysaccharide ...(LPS)-induced acute lung injury (ALI) in mice. Acute lung injury (ALI) was induced
via
the intratracheal administration of LPS, and esculetin (20 and 40 mg/kg) was given intraperitoneally 30 min before LPS challenge. After 6 h of LPS administration, lung tissues were collected for analysis. Pretreatment with esculetin significantly attenuated histopathological changes, inflammatory cell infiltration, and production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, in the lung tissue. Furthermore, esculetin inhibited the protein kinase B (AKT), extracellular signal-regulated kinase (ERK), and nuclear factor-kappa B (NF-κB) pathways and downregulated the expression of RORγt and IL-17 in LPS-induced ALI. Our results indicated that esculetin possesses anti-inflammatory and protective effects against LPS-induced ALI
via
inhibition of the AKT/ERK/NF-κB and RORγt/IL-17 pathways.
The correlation between the clinical manifestations and fecal viral load of norovirus (NoV) infection remains unknown.
We established a SYBR® Green-based real-time quantitative reverse transcriptase ...polymerase chain reaction (qRT-PCR) method to quantify NoV and then sequenced its genomes from the feces of patients admitted at the Chang Gung Memorial Hospital from 2017 to 2018.
NoV GII.4 Sydney (n = 21, 36.2%) and GII.P16-GII.2 (n = 19, 32.8%), the two predominant genotypes found among 58 isolates, were closely related to the Taiwan variant 2012a cluster in the VP1 region and genotypes of China strain. An increase in viral load could be observed on Day 3 following the onset of NoV infection. The viral load then declined rapidly from days 10–15 but remained high for >1 month in a severe combined immunodeficiency patient. Significantly longer shedding was found in patients with fever (p = 0.03) or infected by the GII.4 Sydney strain (p < 0.01).
The qRT-PCR-mediated method proposed in this work could quantify the viral load in patients with NoV infection. Significant viral shedding over a period of 2 weeks in children with acute gastroenteritis and >1 month in an immunodeficient patient was observed. Significantly longer shedding could be correlated with infection by the GII.4 Sydney strain and febrile patients.
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