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Background Chronic kidney disease (CKD) is pathologically correlated with a sophisticated milieu of innate and adaptive immune dysregulation, but the underlying immunological disturbances remain poorly understood. Methods To address this, we comprehensively interrogated cellular and soluble elements of the immune system by using high-dimensional flow cytometry to analyze peripheral blood mononuclear cells and performing cytokine/chemokine profiling of serum samples, respectively, in a cohort of 69 patients and 19 non-CKD controls. Results Altered serum levels of several cytokines/chemokines were identified, among which concentrations of stem cell factor (SCF) were found to be elevated with the progression of CKD and inversely correlated with estimated glomerular filtration rate (eGFR). Deep immunophenotyping analyses reveal a global change in immune modulation associated with CKD severity. Specifically, a decrease in the subsets of CD56dim natural killer (NK) cells (KLRG-1+CD38+CD64+CD15+CD197+) and monocytes (KLRG-1+CD38+PD-1+) was detected in severe CKD compared with controls and mild CKD. In addition, comparisons between mild and severe CKD demonstrated a loss of a mature B cell population (PD-1+CD197+IgD+HLA-DR+) in the advanced stages of disease. Further, we identified immunophenotypic markers to discriminate mild CKD from the controls, among which the portion of CD38+ monocytes was of particular value in early diagnosis. Conclusions Our data unveil severity-specific immunological signatures perturbed in CKD patients.

Purpose: Sunitinib is currently considered as the standard treatment for advanced renal cell carcinoma (RCC). We aimed to better understand the mechanisms of sunitinib action in kidney cancer treatment and in the development of acquired resistance.Experimental Design: Gene expression profiles of RCC tumor endothelium in sunitinib-treated and -untreated patients were analyzed and verified by quantitative PCR and immunohistochemistry. The functional role of the target gene identified was investigated in RCC cell lines and primary cultures in vitro and in preclinical animal models in vivo.Results: Altered expression of autotaxin, an extracellular lysophospholipase D, was detected in sunitinib-treated tumor vasculature of human RCC and in the tumor endothelial cells of RCC xenograft models when adapting to sunitinib. ATX and its catalytic product, lysophosphatidic acid (LPA), regulated the signaling pathways and cell motility of RCC in vitro. However, no marked in vitro effect of ATX-LPA signaling on endothelial cells was observed. Functional blockage of LPA receptor 1 (LPA1) using an LPA1 antagonist, Ki16425, or gene silencing of LPA1 in RCC cells attenuated LPA-mediated intracellular signaling and invasion responses in vitro. Ki16425 treatment also dampened RCC tumorigenesis in vivo. In addition, coadministration of Ki16425 with sunitinib prolonged the sensitivity of RCC to sunitinib in xenograft models, suggesting that ATX-LPA signaling in part mediates the acquired resistance against sunitinib in RCC.Conclusions: Our results reveal that endothelial ATX acts through LPA signaling to promote renal tumorigenesis and is functionally involved in the acquired resistance of RCC to sunitinib. Clin Cancer Res; 19(23); 6461–72. ©2013 AACR.

PDF file 142K, Supplemental Materials and Methods, Supplemental Table S1-S2, and Supplemental Figure Legends Supplemental Table 1. Quantitative analysis of ENPP2 mRNA expression in tumor and normal renal endothelial cells. Endothelial cells from human RCC specimens (T) and their normal counterparts (N) were isolated from a single-cell suspension using anti-CD31-coated magnetic beads. Total RNA was prepared and real-time RT-PCR was performed for ENPP2 and GAPDH. Supplemental Table 2. The expression level of LPA1-4 is determined by real-time PCR. Part of results was confirmed by western blot. +++, average Ct < 31; +, average Ct ranges from 31 to 38; -, average Ct > 38 when average Ct of GAPDH ranges between 18 and 21, which is served as an internal control

BACKGROUND/PURPOSE Genetic and environmental factors play significant roles in the pathogenesis of Parkinson's disease (PD). Recently, 17 novel risk loci of PD were identified in a meta-analysis of genome-wide association study (GWAS) in the European populations. In order to clarify if these risk loci are associated with PD in Taiwanese population, we conducted a case-control study including 14 of the novel risk loci and analyzed the genetic distribution and allele frequency. METHODS A total of 2798 subjects were recruited in this study. Genotyping was performed in 672 PD patients and 609 healthy controls by using Mass ARRAY, and data of another 1517 healthy controls from Taiwan Biobank were also examined. RESULTS Our results show that the dominant models of ITPKB rs4653767 (OR (95% CI) = 0.832 (0.699, 0.990), p = 0.038), IL1R2 rs34043159 (OR (95% CI) = 0.812 (0.665, 0.992), p = 0.041) and COQ7 rs11343 (OR (95% CI) = 0.304 (0.180, 0.512), p

Colorectal cancer (CRC) is a commonly occurring tumor type worldwide, and its development is governed by a connection between genetic variations and acquired factors. Carbonic anhydrase 9 (CA9) is a cell-surface pH modulator that has been demonstrated to contribute to key steps of cancer progression. Here, we attempted to interrogate the effect of

Gambogic acid (GA), a natural and bioactive compound from the gamboge resin, has been reported to exhibit many oncostatic activities against several types of malignancies. However, its effects on the progression of oral squamous cell carcinoma (OSCC) remain largely unexplored. To fill this gap, we investigated the anticancer role of GA and molecular mechanisms underlying GA’s actions in combating oral cancer. We found that GA negatively regulated the viability of OSCC cells, involving induction of the sub-G1 phase and cell apoptosis. In addition, a specific signature of apoptotic proteome, such as upregulation of heme oxygenase-1 (HO-1) and activation of caspase cascades, was identified in GA-treated OSCC. Moreover, such induction of HO-1 expression and caspase cleavage by GA was significantly diminished through the pharmacological inhibition of p38 kinase. In conclusion, these results demonstrate that GA promotes cell apoptosis in OSCC, accompanied with the activation of a p38-dependent apoptotic pathway. Our findings provide potential avenues for the use of GA with high safety and therapeutic implications in restraining oral cancer.

Perturbation of gut dysbiosis has been linked to chronic kidney disease (CKD), a gradual loss of renal function that was pathologically correlated with a sophisticated milieu of metabolic and immune dysregulation. However, the underlying host-microbe interaction is poorly understood. To address this, we performed multi-omics measurements, including systems-level gut microbiome, targeted serum metabolome, and deep immunotyping, in a cohort of 72 patients and 20 non-CKD controls. Our analyses on functional profiles of gut microbiome showed that loss of renal function decreased the diversity and abundance of carbohydrate-active enzyme (CAZyme) genes, whereas kidney failure increased the abundance of antibiotic resistance, nitrogen cycling enzyme, and virulence factor genes. Moreover, use of fecal metagenomic, serum metabolomic, and immune signatures resulted in distinct effects on differentiating mild and severe CKD from controls. Models generated using measurements of serum metabolites (amino acids, bile acids, and short-chain fatty acids) or immunotypes were predictive of renal impairment but less so than many of functional profiles derived from gut microbiota, with the CAZyme genes being the top performing model to accurately predict early stage of diseases. In addition, correlation analyses among systems-level microbiome, serum metabolome, and immune parameters revealed coordinated host-microbe relationships in CKD. Specifically, the highest fractions of significant correlations were identified with circulating metabolites by several taxonomic and functional profiles of gut microbiome, while immunotype features were only moderately associated with the abundance of microbiome-encoded metabolic pathways and serum levels of amino acids (e.g., B cell cluster-tryptophan and B cell cluster-tryptophan metabolism). Overall, our multi-omics integration revealed several signatures of systems-level gut microbiome in robust associations with host-microbe co-metabolites and renal function, which may be of etiological and diagnostic implications in CKD.

Introduction Variants in the low-density lipoprotein receptor–related protein 10 (LRP10), linked to inherited forms of α-synucleinopathies, have been reported. Nine variants of LRP10 were identified in the first such report, and subsequent studies have identified possible pathogenic variants in patients with sporadic Parkinson's disease (PD). Few studies have investigated the role of LRP10 in PD. We sought to validate the role of this gene in Taiwanese patients with PD. Methods In total, 1277 individuals were included in this study (669 had PD and 608 were controls). The entire LRP10 coding exons and exon–intron boundaries were sequenced in 103 probands with early-onset PD or familial PD. We then genotyped the newly identified variants from the 103 patients and previously reported potential pathogenic variants in our cohort. The frequencies of variants were analyzed. Results Five new and possibly pathogenic variants were identified initially. In total, 14 potentially pathogenic variants (including nine previously reported and five newly identified variants) were analyzed thereafter. We did not find any significant associations between any variant and the risk of PD. However, c.1424+5delG was identified in a patient with sporadic PD who was diagnosed as having PD and dementia and who had prominent psychiatric symptoms. Conclusion Although we identified a patient with sporadic PD and dementia carrying a c.1424+5delG variant, our data did not provide sufficient evidence to support the role of LRP10 in PD in Taiwanese adults.

Cell surface glycosylation has been known as an important modification process that can be targeted and manipulated by malignant cells to escape from host immunosurveillance. We previously showed that the blood group branched I antigen on the leukemia cell surface can regulate the cell susceptibility against natural killer (NK) cell-mediated cytotoxicity through interfering target–NK interaction. In this work, we first identified N-linkage as the major glycosylation linkage type for branched I glycan formation on leukemia cells, and this linkage was responsible for cell sensitivity against therapeutic NK-92MI targeting. Secondly, by examining different leukemia cell surface death receptors, we showed death receptor Fas had highest expressions in both Raji and TF-1a cells. Mutations on two Fas extracellular N-linkage sites (118 and 136) for glycosylation impaired activation of Fas-mediated apoptosis during NK-92MI cytotoxicity. Last, we found that the surface I antigen expression levels enable leukemia cells to respond differently against NK-92MI targeting. In low I antigen expressing K-562 cell, reduction of I antigen presence greatly reduced leukemia cell susceptibility against NK-92MI targeting. But in other high I antigen expressing leukemia cells, similar reduction in I antigen expression did not affect cell susceptibility.

Background: Although associations between low protein diet (LPD) and changes of gut microbiota have been reported; however, systematic discernment of the effects of LPD on diet-microbiome-host interaction in patients with chronic kidney disease (CKD) is lacking. Methods: We searched PUBMED and EMBASE for articles published on changes of gut microbiota associated with implementation of LPD in CKD patients until July 2021. Independent researchers extracted data and assessed risks of bias. We conducted meta-analyses of combine p-value, mean differences and random effects for gut microbiota and related metabolites. Study heterogeneity was measured by Tau2 and I2 statistic. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: Five articles met inclusion criteria. The meta-analyses of gut microbiota exhibited enrichments of Lactobacillaceae (meta-p= 0.010), Bacteroidaceae (meta-p= 0.048) and Streptococcus anginosus (meta-p< 0.001), but revealed depletion of Bacteroides eggerthii (p=0.017) and Roseburia faecis (meta-p=0.019) in LPD patients compared to patients undergoing normal protein diet. The serum IS levels (mean difference: 0.68 ug/mL, 95% CI: -8.38-9.68, p= 0.89) and pCS levels (mean difference: -3.85 ug/mL, 95% CI: -15.49-7.78, p < 0.52) did not change between groups. We did not find significant differences on renal function associated with change of microbiota between groups (eGFR, mean difference: -7.21 mL/min/1.73 m2, 95% CI: -33.2-18.79, p= 0.59; blood urea nitrogen, mean difference: -6.8 mg/dL, 95% CI: -46.42-32.82, p= 0.74). Other clinical (sodium, potassium, phosphate, albumin, fasting sugar, uric acid, total cholesterol, triglycerides, C-reactive protein and hemoglobin) and anthropometric estimates (body mass index, systolic blood pressure and diastolic blood pressure) did not differ between the two groups. Conclusions: This systematic review and meta-analysis suggested that the effects of LPD on the microbiota were observed predominantly at the families and species levels but minimal on microbial diversity or richness. In the absence of global compositional microbiota shifts, the species-level changes appear insufficient to alter metabolic or clinical outputs.

First discovered on the natural killer (NK) cell, the cell surface inhibitory receptor sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7) is known for regulating many important biological activities. However, the detail regulatory mechanism for Siglec-7 expression in NK cells currently remains unclear. In this study, we aimed to investigate how cell surface Siglec-7 expression is regulated and found that, in both NK cell lines and peripheral NK cells, transcription was the main regulatory step. Furthermore, when NK-92MI and peripheral NK cells were treated with DNA methyltransferase (DNMT) inhibitor, the CpG island, with 9 CpG sites, in 5' Siglec-7 promoter became noticeably hypomethylated, and Siglec-7 expression increased in both RNA transcript and surface protein. Within this CpG island, we identified both CpG 8 and CpG 9 as two key regulators responsible for Siglec-7 expression. Additionally, by using histone deacetylases (HDAC) inhibitor, butyric acid, we showed that Siglec-7 expression was also subjected to the histone modification. And a combined treatment with both 5-azacytidine and butyric acid showed an additive effect on Siglec-7 transcript expression in peripheral NK cells.

Chronic kidney disease (CKD) is a serious healthcare dilemma, associated with specific changes in gut microbiota and circulating metabolome. Yet, the functional capacity of CKD microbiome and its intricate relationship with the host metabolism at different stages of disease are less understood. Methods Here, shotgun sequencing of fecal samples and targeted metabolomics profiling of serum bile acids, short- and medium-chain fatty acids, and uremic solutes were performed in a cohort of CKD patients with different severities and non-CKD controls. Results We identified that levels of 13 microbial species and 6 circulating metabolites were significantly altered across early to advanced stages or only in particular stage(s). Among these, Prevotella sp. 885 (decreased) was associated with urea excretion, while caproic acid (decreased) and p-cresyl sulfate (elevated) were positively and negatively correlated with the glomerular filtration rate, respectively. In addition, we identified gut microbial species linked to changes in circulating metabolites. Microbial genes related to secondary bile acid biosynthesis were differentially abundant at the early stage, while pathway modules related to lipid metabolism and lipopolysaccharide biosynthesis were enriched in the CKD microbiome at the advanced stage, suggesting that changes in microbial metabolism and host inflammation may contribute to renal health. Further, we identified metagenomic and metabolomic markers to discriminate cases of different severities from the controls, among which Bacteroides eggerthii individually was of particular value in early diagnosis. Conclusions Our dual-omics data reveal the connections between intestinal microbes and circulating metabolites perturbed in CKD, which may be of etiological and diagnostic importance.

Hepatocellular carcinoma (HCC) is a major malignancy of cancer-related mortality worldwide. Metastasis-associated in colon cancer-1 (MACC1) was suggested as a marker for vascular invasive HCC. This study investigated the MACC1 single-nucleotide polymorphisms (SNPs) to evaluate HCC susceptibility and clinicopathological characteristics. In this study, real-time polymerase chain reaction was applied to analyze five SNPs of MACC1 rs1990172, rs975263, rs3095007, rs4721888, and rs3735615 in 378 patients with HCC and 1199 cancer-free controls. The results showed that in 151 HCC patients among smokers who carried MACC1 rs1990172 "CA + AA" variants had a lower risk of developing a large tumor (odds ratio [OR] = 0.375, p = 0.026), more advanced clinical stage ([OR] = 0.390, p=0.032), and vascular invasion ([OR] = 0.198, p = 0.034). In 137 HCC patients among drinkers who carried MACC1 rs4721888 "GC + CC" variants had a higher risk to develop vascular invasion ([OR] = 3.780, p = 0.009). Further analyses revealed a statistical significance of aberrant AST/ALT ratio in HCC patients with MACC1 rs975263 "AG+GG" variants before adjustment of age and alcohol drinking. In conclusion, our results suggested that the MACC1 SNPs rs1990172, rs4721888, and rs975263 are involved in HCC progression and clinical characteristics. MACC1 polymorphisms may serve as a marker or a predictor to evaluate HCC progression and prognosis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Current studies have suggested that the pathobiology of drug-mediated SJS/TEN involves a dysregulation of cellular immunity with overwhelming activation of cytotoxic T lymphocytes. The canonical Wnt signaling pathway plays important roles in T cell development and activation, which may provide potential avenues for alleviating dysregulated immunity in SJS/TEN. In this study, we aimed to assess the implication of Wnt signaling in drug-reactive T cells in SJS/TEN. We showed downregulation of Wnt signaling components, including T cell factor 1 (TCF-1)/lymphoid enhancer binding factor 1 (LEF-1) transcription factors, in SJS/TEN patients, suggesting that canonical Wnt signaling is regulated during cytotoxic T cell responses in SJS/TEN. Further analyses demonstrated that engagement of the T cell receptor by antigen encounter and treatment of a prognostic marker of SJS/TEN, IL-15, in vitro led to the downregulation of LEF-1 and TCF-1 expression in CD8+ T cells. Enhancement of Wnt signaling by adding the Wnt activators attenuated ex vivo activation of drug-specific T cells from SJS/TEN patients, indicating a functional involvement of Wnt signaling in the pathomechanism of SJS/TEN. These findings provide additional insight into the immunopathogenesis and therapeutic intervention of this devastating condition.

Psoriasis is a chronic inflammatory disease which is caused by the interaction between genetic and environmental factors. Evidence shows an association of psoriasis with co-morbidities including cardiovascular diseases, metabolic syndrome and hyperuricemia. Genome-wide association studies have revealed that the ABCG2 gene encoding ATP-binding cassette G2 protein was associated with inflammation and higher serum urate concentrations. In this study, we aimed to evaluate the role of ABCG2 gene polymorphisms on the susceptibility to psoriasis. The genotype distribution of two ABCG2 single nucleotide polymorphisms (SNPs), rs2231142 and rs2231137, was examined in 410 psoriasis patients and 1,089 gender-matched non-psoriasis controls. We found that heterozygotes (GT) for rs2231142 was associated with a decreased risk of psoriasis (p = 0.001; adjusted OR = 0.532; 95% CI, 0.370–0.765) after adjusting for age, as compared with homozygotes for the major allele (GG). Subjects who carried at least one polymorphic allele (homozygote or heterozygote for the minor allele) were less susceptible to psoriasis (p = 0.002; adjusted OR = 0.594; 95% CI, 0.249–0.823) and bearing higher serum urate levels (p = 0.026) than those homozygous for the major allele. Our results indicated that the ABCG2 gene polymorphism was associated with the risk of psoriasis.

Magnolol is a natural compound extracted from Chinese herbal medicine and can induce apoptosis in numerous types of cancer cells. However, the molecular mechanisms of magnolol in oral cancer are still unclear. In this study, we investigated the anti-cancer effects and underlying mechanisms of magnolol in human oral cancer cell lines. Our results exhibited that magnolol inhibited the cell proliferation via inducing the sub-G1 phase and cell apoptosis of HSC-3 and SCC-9 cells. The human apoptosis array and Western blot assay showed that magnolol increased the expression of cleaved caspase-3 proteins and heme oxygenase-1 (HO-1). Moreover, we proved that magnolol induces apoptosis in oral cancer cell lines via the c-Jun N-terminal kinase (JNK)1/2 and p38 pathways. Overall, the current study supports the role for magnolol as a therapeutic approach for oral cancer through JNK1/2- and p38-mediated caspase activation.

Osteoarthritis (OA), the most common arthritis worldwide, is a degenerative joint disease characterized by progressive cartilage breakdown, subchondral remodeling, and synovial inflammation. Although conventional pharmaceutical therapies aimed to prevent further cartilage loss and joint dysfunction, there are no ideal strategies that target the pathogenesis of OA. Melatonin exhibits a variety of regulatory properties by binding to specific receptors and downstream molecules and exerts a myriad of receptor-independent actions via intracellular targets as a chondrocyte protector, an anti-inflammation modulator, and a free radical scavenger. Melatonin also modulates cartilage regeneration and degradation by directly/indirectly regulating the expression of main circadian clock genes, such as transcriptional activators [brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein (Bmal) and circadian locomotor output cycles kaput (Clock)], transcriptional repressors [period circadian regulator (Per)1/2, cryptochrome (Cry)1/2, and Dec2], and nuclear hormone receptors [Rev-Erbs and retinoid acid-related orphan receptors (Rors)]. Owing to its effects on cartilage homeostasis, we propose a potential role for melatonin in the prevention and therapy of OA via the modulation of circadian clock genes, mitigation of chondrocyte apoptosis, anti-inflammatory activity, and scavenging of free radicals.

The inhibitory effect of melatonin on cancer cell dissemination is well established, yet the functional involvement of lncRNAs in melatonin signaling remains poorly understood. In this study, we identified a melatonin-attenuated lncRNA acting as a potential melatonin-regulated oral cancer stimulator (MROS-1). Downregulation of MROS-1 by melatonin suppressed TPA-induced oral cancer migration through replenishing the protein expression of prune homolog 2 (PRUNE2), which functioned as a tumor suppressor in oral cancer. Melatonin-mediated MROS-1/PRUNE2 expression and cell motility in oral cancer were regulated largely through the activation of JAK-STAT pathway. In addition, MROS-1, preferentially localized in the nuclei, promoted oral cancer migration in an epigenetic mechanism in which it modulates PRUNE2 expression by interacting with a member of the DNA methylation machinery, DNA methyltransferase 3A (DNMT3A). Higher methylation levels of PRUNE2 promoter were associated with nodal metastases and inversely correlated with PRUNE2 expression in head and neck cancer. Collectively, these findings suggest that MROS-1, serving as a functional mediator of melatonin signaling, could predispose patients with oral cancer to metastasize and may be implicated as a potential target for antimetastatic therapies.

Geraniin has been reported to have numerous biological activities, including antiviral, antihypertensive, antihyperglycaemic, liver protective, antidiabetic, and apoptotic activities. However, the anti-migration effects of geraniin on oral cancer remain elusive. In this study, we revealed the potential antitumor mechanisms of geraniin through the inhibition of the migration and invasion of human oral cancer cell lines SCC-9 and SCC-14. The results of gelatin zymography and Western blot assays revealed that geraniin significantly reduced the activity and expression of matrix metalloproteinase-2 (MMP-2) of oral cancer cells in a concentration-dependent manner. Furthermore, geraniin potently suppressed the phosphorylation of focal adhesion kinase (FAK), Src, and extracellular signal-regulated kinase (ERK)1/2 but did not affect the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase 1/2. Moreover, blocking the MAPK/ERK1/2 pathway significantly enhanced the anti-migration ability of geraniin in oral cancer cells. In conclusion, we demonstrated that geraniin inhibits the motility of SCC-9 and SCC-14 cells in vitro through a molecular mechanism that involves the attenuation of MMP-2 expression and activity mediated by decreased FAK/Src and ERK1/2 pathways.

Childhood cancer management has improved considerably, with the overall objective of preventing early-life cancers completely. However, cancer remains a major cause of death in children, with the survivors developing anticancer treatment-specific health problems. Therefore, the anticancer treatment needs further improvement. Melatonin is a effective antioxidant and circadian pacemaker. Through multiple mechanisms, melatonin has significant positive effects on multitude adult cancers by increasing survival and treatment response rates, and slowing disease progression. In addition, melatonin appears to be safe for children. As an appealing therapeutic agent, we herein address several key concerns regarding melatonin's potential for treating children with cancer.

In Taiwan, the incidence rate of oral cancer is constantly increasing. Polymorphisms and lifestyle habits are major contributing factors to the development of oral cancer in such cases. Casein kinase 1 epsilon (CK1ε) gene expression plays a role in numerous cancers, and the knockdown of CK1ε induces tumor cell-selective cytotoxicity. The present study was designed to determine the effects of CK1ε gene polymorphisms combined with environmental carcinogens on susceptibility to developing oral squamous cell carcinoma and its clinicopathological status. Four single-nucleotide polymorphisms (SNPs) in CK1ε gene (rs135745, rs135764, rs1997644 and rs2075984) from 741 oral cancer patients and 462 healthy controls were analyzed using real-time polymerase chain reaction. Our results shown that variant types (GC) of CK1ε polymorphic rs135745 exhibited a significantly higher risk of 1.41 (95% confidence interval [CI]: 1.036-1.919) for oral cancer than did wild type alleles. Furthermore, these CK1ε gene SNPs along with betel-quid chewing and/or tobacco use further increased susceptibility to oral cancer. Moreover, variant genotypes (GC+CC) of CK1ε rs135745 were significantly associated with lymph node metastasis. These results suggested that the CK1ε gene polymorphism is associated with the clinicopathological development of oral cancer and increases individuals' susceptibility to environmental carcinogens (e.g., smoking and betel-quid chewing) in terms of developing oral cancer.

Colorectal cancer (CRC) is the third most common cause of cancer mortality worldwide and the most prevalent cancer in Taiwan. The matrix metalloproteinase (MMP)-11 is a proteolytic enzyme of the MMP family which is involved in extracellular matrix degradation and tissue remodeling. In this study, we focused on the associations of MMP-11 single-nucleotide polymorphisms (SNPs) with CRC susceptibility and clinicopathological characteristics. The MMP-11 SNPs rs131451, rs738791, rs2267029, rs738792, and rs28382575 in 479 controls and 479 patients with CRC were analyzed with real-time polymerase chain reaction. We found that the MMP-11 SNP rs738792 “TC + CC” genotype was significantly associated with perineural invasion in colon cancer patients after controlling for clinical parameters [OR (95% CI) = 1.783 (1.074–2.960); p = 0.025]. The MMP-11 rs131451 “TC + CC” genotypic variants were correlated with greater tumor T status [OR (95% CI):1.254 (1.025–1.534); p = 0.028] and perineural invasion [OR (95% CI):1.773 (1.027–3.062); p = 0.040) in male CRC patients. Furthermore, analyses of The Cancer Genome Atlas (TCGA) revealed that MMP-11 levels were upregulated in colorectal carcinoma tissue compared with normal tissues and were correlated with advanced stage, larger tumor sizes, and lymph node metastasis. Moreover, the data from the Genotype-Tissue Expression (GTEx) database exhibited that the MMP-11 rs738792 “CC” and “CT” genotypic variants have higher MMP-11 expression than the “TT” genotype. In conclusion, our results have demonstrated that the MMP-11 SNPs rs738792 and rs131451 may have potential to provide biomarkers to evaluate CRC disease progression, and the MMP-11 rs131451 polymorphism may shed light on sex discrepancy in CRC development and prognosis.

Motivation We proposed a wiSDOM (web-based inclusionary analysis Suite for Disease-Oriented Metagenomics) R Shiny application which comprises six functional modules: (i) initial visualization of sampling effort and distribution of dominant bacterial taxa among groups or individual samples at different taxonomic levels; (ii) statistical and visual analysis of α diversity; (iii) analysis of similarity (ANOSIM) of β diversity on UniFrac, Bray-Curtis, Horn-Morisita or Jaccard distance and visualizations; (iv) microbial biomarker discovery between two or more groups with various statistical and machine learning approaches; (v) assessment of the clinical validity of selected biomarkers by creating the interactive receiver operating characteristic (ROC) curves and calculating the area under the curve (AUC) for binary classifiers; and lastly (vi) functional prediction of metagenomes with PICRUSt or Tax4Fun. Results The performance of wiSDOM has been evaluated in several of our previous studies for exploring microbial biomarkers and their clinical validity as well as assessing the alterations in bacterial diversity and functionality. The wiSDOM can be customized and visualized as per users’ needs and specifications, allowing researchers without programming background to conduct comprehensive data mining and illustration using an intuitive browser-based interface. Availability and implementation The browser-based R Shiny interface can be accessible via (https://lun-ching.shinyapps.io/wisdom/) and freely available at (https://github.com/lunching/wiSDOM). Supplementary information Supplementary data are available at Bioinformatics online.

Summary In this article, we introduce a hierarchical clustering and Gaussian mixture model with expectation-maximization (EM) algorithm for detecting copy number variants (CNVs) using whole exome sequencing (WES) data. The R shiny package ‘HCMMCNVs’ is also developed for processing user-provided bam files, running CNVs detection algorithm and conducting visualization. Through applying our approach to 325 cancer cell lines in 22 tumor types from Cancer Cell Line Encyclopedia (CCLE), we show that our algorithm is competitive with other existing methods and feasible in using multiple cancer cell lines for CNVs estimation. In addition, by applying our approach to WES data of 120 oral squamous cell carcinoma (OSCC) samples, our algorithm, using the tumor sample only, exhibits more power in detecting CNVs as compared with the methods using both tumors and matched normal counterparts. Availability and implementation HCMMCNVs R shiny software is freely available at github repository https://github.com/lunching/HCMM_CNVs.and Zenodo https://doi.org/10.5281/zenodo.4593371. Supplementary information Supplementary data are available at Bioinformatics online.

Dysbiosis of oral microbiome may dictate the progression of oral squamous cell carcinoma (OSCC). Yet, the composition of oral microbiome fluctuates by saliva and distinct sites of oral cavity and is affected by risky behaviors (smoking, drinking and betel quid chewing) and individuals’ oral health condition. To characterize the disturbances in the oral microbial population mainly due to oral tumorigenicity, we profiled the bacteria within the surface of OSCC lesion and its contralateral normal tissue from discovery (n = 74) and validation (n = 42) cohorts of male patients with cancers of the buccal mucosa. Significant alterations in the bacterial diversity and relative abundance of specific oral microbiota (most profoundly, an enrichment for genus Fusobacterium and the loss of genus Streptococcus in the tumor sites) were identified. Functional prediction of oral microbiome shown that microbial genes related to the metabolism of terpenoids and polyketides were differentially enriched between the control and tumor groups, indicating a functional role of oral microbiome in formulating a tumor microenvironment via attenuated biosynthesis of secondary metabolites with anti-cancer effects. Furthermore, the vast majority of microbial signatures detected in the discovery cohort was generalized well to the independent validation cohort, and the clinical validity of these OSCC-associated microbes was observed and successfully replicated. Overall, our analyses reveal signatures (a profusion of Fusobacterium nucleatum CTI-2 and a decrease in Streptococcus pneumoniae) and functions (decreased production of tumor-suppressive metabolites) of oral microbiota related to oral cancer.

Melatonin is an indole produced by the pineal gland at night under normal light or dark conditions, and its levels, which are higher in children than in adults, begin to decrease prior to the onset of puberty and continue to decline thereafter. Apart from circadian regulatory actions, melatonin has significant apoptotic, angiogenic, oncostatic, and antiproliferative effects on various cancer cells. Particularly, the ability of melatonin to inhibit skeletomuscular sarcoma, which most commonly affects children, teenagers, and young adults, is substantial. In the past few decades, the vast majority of references have focused on the concept of epithelial–mesenchymal transition involvement in invasion and migration to allow carcinoma cells to dissociate from each other and to degrade the extracellular matrix. Recently, researchers have applied this idea to sarcoma cells of mesenchymal origin, e.g., osteosarcoma and Ewing sarcoma, with their ability to initiate the invasion-metastasis cascade. Similarly, interest of the effects of melatonin has shifted from carcinomas to sarcomas. Herein, in this state-of-the-art review, we compiled the knowledge related to the molecular mechanism of antimetastatic actions of melatonin on skeletomuscular sarcoma as in childhood and during adolescence. Utilization of melatonin as an adjuvant with chemotherapeutic drugs for synergy and fortification of the antimetastatic effects for the reinforcement of therapeutic actions are considered.

To develop a pre-emptive genetic test that comprises multiple predisposing alleles for the prevention of phenytoin-related severe cutaneous adverse reactions (SCARs), three sets of patients with phenytoin-SCAR and drug-tolerant controls from Taiwan, Thailand, and Japan, were enrolled for this study. In addition to cytochrome P450 (CYP)2C9*3, we found that HLA-B*13:01, HLA-B*15:02, and HLA-B*51:01 were significantly associated with phenytoin hypersensitivity with distinct phenotypic specificities. Strikingly, we showed an increase in predictive sensitivity of concurrently testing CYP2C9*3/HLA-B*13:01/HLA-B*15:02/HLA-B*51:01 from 30.5-71.9% for selecting the individuals with the risk of developing phenytoin-SCAR in Taiwanese cohorts, accompanied by a specificity of 77.7% (combined sensitivity, 64.7%; specificity, 71.9% for three Asian populations). Meta-analysis of the four combined risk alleles showed significant associations with phenytoin-SCAR in three Asian populations. In conclusion, combining the assessment of risk alleles of HLA and CYP2C9 potentiated the usefulness of predictive genetic tests to prevent phenytoin hypersensitivity in Asians.

Matrix metalloproteinases (MMPs) play a major role in extracellular matrix remodeling and are involved in tumor cell invasion. Cancers such as childhood leukemia are characterized by their capacity to infiltrate different organs. MMP production by leukemic cells may indicate a leukemic subtype or subpopulation with a more invasive phenotype. Therefore, clarifying the action mechanisms of MMPs as prognostic predictors or MMP targeting as a therapeutic strategy is necessary. MMP-targeting drugs have been developed for the treatment of hematological malignancies. In this review, we highlight current advances in understanding the molecular mechanisms and pathological characteristics of various MMPs, as well as recent therapeutic advances targeting MMPs in childhood leukemia. Several studies have been conducted on the therapeutic efficacy of MMP inhibitors in cancer, such as collagen peptidomimetics, nonpeptidomimetic inhibitors of MMP active sites, bisphosphonates, and tetracycline derivatives. Here, we conclude that more clinical trials are necessary to estimate the role of selective MMP inhibitors in the treatment and prevention of childhood leukemia.

Specific ethnic genetic backgrounds are associated with the risk of Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) especially in Asians. However, there have been no large cohort, multiple-country epidemiological studies of medication risk related to SJS/TEN in Asian populations. Thus, we analyzed the registration databases from multiple Asian countries who were treated during 1998-2017. A total 1,028 SJS/TEN cases were identified with the algorithm of drug causality for epidermal necrolysis. Furthermore, those medications labeled by the US Food and Drug Administration (FDA) as carrying a risk of SJS/TEN were also compared with the common causes of SJS/TEN in Asian countries. Oxcarbazepine, sulfasalazine, COX-II inhibitors, and strontium ranelate were identified as new potential causes. In addition to sulfa drugs and beta-lactam antibiotics, quinolones were also a common cause. Only one acetaminophen-induced SJS was identified, while several medications (e.g., oseltamivir, terbinafine, isotretinoin, and sorafenib) labeled as carrying a risk of SJS/TEN by the FDA were not found to have caused any of the cases in the Asian countries investigated in this study.

Dapsone-induced hypersensitivity reactions may cause severe cutaneous adverse reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS). It has been reported that HLA-B*13:01 is strongly associated with dapsone-induced hypersensitivity reactions among leprosy patients. However, the phenotype specificity and detailed immune mechanism of HLA-B*13:01 remain unclear. We investigated the genetic predisposition, HLA-B*13:01 function, and cytotoxic T cells involved in the pathogenesis of dapsone-induced severe cutaneous adverse reactions. We enrolled patients from Taiwan and Malaysia with DRESS and maculopapular eruption with chronic inflammatory dermatoses. Our results showed that the HLA-B*13:01 allele was present in 85.7% (6/7) of patients with dapsone DRESS (odds ratio = 49.64, 95% confidence interval = 5.89–418.13; corrected P = 2.92 × 10–4) but in only 10.8% (73/677) of general population control individuals in Taiwan. The level of granulysin, the severe cutaneous adverse reaction-specific cytotoxic protein released from cytotoxic T cells, was increased in both the plasma of DRESS patients (36.14 ± 9.02 ng/ml, P

Objectives Both genetic and environmental factors are conceivably required to assess the prognosis of oral squamous cell carcinoma (OSCC), yet little is known regarding the relationship between oral microbiome and the mutational spectrum of OSCC. Materials and methods Here, we used 16S rRNA amplicon sequencing to study the composition of oral microorganisms in OSCC patients, whose cancer mutational profiles were previously defined by whole-exome sequencing, to evaluate the relationship between oral microbiome and the mutational changes in OSCC. Results Analyzing the contributions of the five mutational signatures extracted from the primary tumors revealed three groups of OSCC (mutational signature cluster, MSC1-3) that were significantly associated with demographic and clinical features. Taxonomic analysis of the predominant phyla in salivary samples showed variation in the relative abundance of Firmicutes and Bacteroidetes in the three MSC groups. In addition, significant differences in bacterial species richness (alpha diversity) and slight sample-to-sample dissimilarities in bacterial community structures (beta diversity) were noted among different MSC groups. Further, predicting the functional capabilities of microbial communities by reconstruction of unobserved states showed that many pathways related to cell motility were differentially enriched among the three MSC groups. Conclusion Collectively, these results indicate a potential association of oral microbiome with the mutational changes in OSCC.

Genetic and acquired factors are thought to be interrelated and imperative to estimate the risk and prognosis of oral squamous cell carcinoma (OSCC). HOX transcript antisense intergenic RNA ( HOTAIR) plays crucial roles in gene regulation and is regulated in a variety of cancers. Polymorphisms in HOTAIR have been recently linked to the predisposition to diverse malignancies. In the present study, we aimed to evaluate the influences of HOTAIR gene polymorphisms, combined with environmental triggers, on the susceptibility to oral tumorigenesis. Four single-nucleotide polymorphisms of the HOTAIR gene— rs920778, rs1899663, rs4759314, and rs12427129—were tested in 1,200 control participants and 907 patients with OSCC. We detected a significant association of rs1899663 with the risk of OSCC (adjusted odds ratio, 2.227; 95% confidence interval [95% CI], 1.197 to 4.146; P = 0.012) after adjustment for 3 potential confounders: smoking, betel quid chewing, and alcohol consumption. In further analyses where habitual exposure to each of 3 environmental factors was excluded, we found that, in addition to rs1899663, non–betel quid users who carried the polymorphic allele of rs920778 were more prone to develop OSCC than were those homozygous for wild-type allele (TC: odds ratio [OR], 1.472; 95% CI, 1.069 to 2.029; P = 0.018; TC+CC: OR, 1.448; 95% CI, 1.060 to 1.977; P = 0.020). Moreover, in exploring the relationship between HOTAIR gene polymorphisms and the clinical status of only patients with OSCC who were non–betel quid chewers (excluding the advanced clinical stage), we found that rs920778 and rs4759314 were correlated with the development of large-size tumors (OR, 1.891; 95% CI, 1.027 to 3.484; P = 0.04) and increased lymph node metastasis (OR, 4.140; 95% CI, 1.785 to 9.602; P = 0.001), respectively. Further functional assessments link rs920778 to the regulation of HOTAIR expression and epigenetic status. Our results reveal an interactive effect of HOTAIR gene polymorphisms and betel quid chewing on the development and progression of oral cancer.

Oral squamous cell carcinoma (OSCC), an epithelial malignancy affecting a variety of subsites in the oral cavity, is prevalent in Asia. The survival rate of OSCC patients has not improved over the past decades due to its heterogeneous etiology, genetic aberrations, and treatment outcomes. Improvement in therapeutic strategies and tailored treatment options is an unmet need. To unveil the mutational spectrum, whole-exome sequencing of 120 OSCC from male individuals in Taiwan was conducted. Analyzing the contributions of the five mutational signatures extracted from the dataset of somatic variations identified four groups of tumors that were significantly associated with demographic and clinical features. In addition, known (TP53, FAT1, EPHA2, CDKN2A, NOTCH1, CASP8, HRAS, RASA1, and PIK3CA) and novel (CHUK and ELAVL1) genes that were significantly and frequently mutated in OSCC were discovered. Further analyses of gene alteration status with clinical parameters revealed that the tumors of the tongue were enriched with copy-number alterations in several gene clusters containing CCND1 and MAP4K2. Through defining the catalog of targetable genomic alterations, 58% of the tumors were found to carry at least one aberrant event potentially targeted by US Food and Drug Administration (FDA)-approved agents. Strikingly, if targeting the p53-cell cycle pathway (TP53 and CCND1) by the drugs studied in phase I-III clinical trials, those possibly actionable tumors are predominantly located in the tongue, suggesting a better prediction of sensitivity to current targeted therapies. Our work revealed molecular OSCC subgroups that reflect etiological and prognostic correlation as well as defined the landscape of major altered events in the coding regions of OSCC genomes. These findings provide clues for the design of clinical trials for targeted therapies and stratification of OSCC patients with differential therapeutic efficacy.

Background Childhood asthma is a multifactorial inflammatory condition of the airways, associated with specific changes in respiratory microbiome and circulating metabolome. Methods To explore the functional capacity of asthmatic microbiome and its intricate connection with the host, we performed shotgun sequencing of airway microbiome and untargeted metabolomics profiling of serum samples in a cohort of children with mite-sensitized asthma and non-asthmatic controls. Results We observed higher gene counts and sample-to-sample dissimilarities in asthmatic microbiomes, indicating a more heterogeneous community structure and functionality among the cases than in controls. Moreover, we identified airway microbial species linked to changes in circulating metabolites and IgE responses of the host, including a positive correlation between Prevotella sp oral taxon 306 and dimethylglycine that were both decreased in patients. Several control-enriched species (Eubacterium sulci, Prevotella pallens, and Prevotella sp oral taxon 306) were inversely correlated with total and allergen-specific IgE levels. Genes related to microbial carbohydrate, amino acid, and lipid metabolism were differentially enriched, suggesting that changes in microbial metabolism may contribute to respiratory health in asthmatics. Pathway modules relevant to allergic responses were differentially abundant in asthmatic microbiome, such as enrichments for biofilm formation by Pseudomonas aeruginosa, membrane trafficking, histidine metabolism, and glycosaminoglycan degradation, and depletions for polycyclic aromatic hydrocarbon degradation. Further, we identified metagenomic and metabolomic markers (eg, Eubacterium sulci) to discriminate cases from the non-asthmatic controls. Conclusions Our dual-omics data reveal the connections between respiratory microbes and circulating metabolites perturbed in mite-sensitized pediatric asthma, which may be of etiological and diagnostic implications.

Ethnopharmacological relevance Salvia miltiorrhiza Bunge, as known as Danshen, has used for the prevention and treatment of cardiovascular diseases clinically and anti-cancer activities. Salvianolic acid A (SAA), one of the most abundant ingredients, hydrophilic derivatives of Salvia miltiorrhiza Bunge, exerts a variety of pharmacological actions, such as anti-oxidative, anti-inflammatory and anti-cancer activities. However, the impact of SAA on nasopharyngeal carcinoma (NPC) invasion and metastasis remains unexplored. Aim of the study To investigate the potential of SAA to prevent migration and invasion on NPC cell. Materials and methods MTT assay and Boyden chamber assay were performed to determine cell proliferation, migration and invasion abilities, respectively. The activity and protein expression of matrix metalloproteinase-2 (MMP-2) were determined by gelatin zymography and western blotting. Results Here, we showed that SAA considerably suppressed the migrative and invasive activity of human NPC cells but not rendered cytotoxicity. In SAA-treated NPC cells, the activity and expression of matrix metalloproteinase-2 (MMP-2), a key regulator of cancer cell invasion, were reduced. Additionally, the presence of high concentrations of SAA dramatically abolished the activation of focal adhesion kinase (FAK) and moderately inhibited the phosphorylation of Src and ERK in NPC cells. Conclusions Our results demonstrated that SAA inhibited the migration and invasion of NPC cells, accompanied by downregulation of MMP-2 and inactivation of FAK, Src, and ERK pathways. These findings indicate a usefulness of SAA on restraining NPC invasion and metastasis.

Lissencephaly (LIS), denoting a "smooth brain," is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1 (also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause of posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice. LIS1 also localizes to the centrosome, suggesting that this organelle is key to the mechanism of posterior predominant LIS.

Betel quid (BQ) chewing is a prevailing risk for oral squamous cell carcinoma (OSCC) in Southeast Asia. Yet, the detailed mechanisms by which BQ chewing damages the genome are still not fully understood. Through exome sequencing of tumor–normal pairs from 196 male patients with OSCC, including 95 habitual BQ chewers and 101 non-BQ users, we conducted a quantitative survey of mutational signatures and genomic aberrations and explored their association with BQ chewing. We found that BQ-associated elevation in mutation rate was seen in cancers of the tongue, but not in overall OSCC. Additionally, we identified a mutational signature that is enriched in tumors from BQ users. Moreover, the numbers of small insertions and deletions (INDELs) and breakpoints derived from structural variations (SV) were increased, whereas the extent of loss of heterozygosity was decreased in BQ-related OSCC genomes. However, neither the number of base substitutions and microsatellite instability events nor the extent of copy-number alterations differed between BQ-related and -unrelated OSCC. In conclusion, consistent with the proposition that BQ chewing increases OSCC risk as a mutagen, our results unveil a BQ-associated mutational signature and indicate mutagenic impacts of BQ chewing on preferentially eliciting INDELs and SV-related breakpoints in OSCC genomes.

Hepatocellular carcinoma (HCC) is a major malignancy of cancer-related mortality worldwide. Metastasis-associated in colon cancer-1 (MACC1) was suggested as a marker for vascular invasive HCC. This study investigated the MACC1 single-nucleotide polymorphisms (SNPs) to evaluate HCC susceptibility and clinicopathological characteristics. In this study, real-time polymerase chain reaction was applied to analyze five SNPs of MACC1 rs1990172, rs975263, rs3095007, rs4721888, and rs3735615 in 378 patients with HCC and 1199 cancer-free controls. The results showed that in 151 HCC patients among smokers who carried MACC1 rs1990172 "CA + AA" variants had a lower risk of developing a large tumor (odds ratio [OR] = 0.375, p = 0.026), more advanced clinical stage ([OR] = 0.390, p=0.032), and vascular invasion ([OR] = 0.198, p = 0.034). In 137 HCC patients among drinkers who carried MACC1 rs4721888 "GC + CC" variants had a higher risk to develop vascular invasion ([OR] = 3.780, p = 0.009). Further analyses revealed a statistical significance of aberrant AST/ALT ratio in HCC patients with MACC1 rs975263 "AG+GG" variants before adjustment of age and alcohol drinking. In conclusion, our results suggested that the MACC1 SNPs rs1990172, rs4721888, and rs975263 are involved in HCC progression and clinical characteristics. MACC1 polymorphisms may serve as a marker or a predictor to evaluate HCC progression and prognosis.

The long noncoding (lnc)RNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), plays a crucial role in the development of hepatocellular carcinoma (HCC). However, potential genetic variants (single nucleotide polymorphisms, SNPs) in MALAT1 that affect the susceptibility and progression of HCC have rarely been explored. Three tagging SNPs, viz., rs3200401 C > T, rs619586 A > G, and rs1194338 C > A, in MALAT1 were genotyped by a TaqMan allelic discrimination assay in 394 HCC patients and 1199 healthy controls. A stratified analysis showed that younger patients (

The interplay of the gut microbes with gut-producing nephrotoxins and the renal progression remains unclear in large human cohort. Significant compositional and functional differences in the intestinal microbiota (by 16S rRNA gene sequencing) were noted among 30 controls and 92 (31 mild, 30 moderate and 31 advanced) patients at different chronic kidney disease (CKD) stages (discovery cohort). A core CKD-associated microbiota consisted of 7 genera (Escherichia_Shigella, Dialister, Lachnospiraceae_ND3007_group, Pseudobutyrivibrio, Roseburia, Paraprevotella and Ruminiclostridium) and 2 species (Collinsella stercoris and Bacteroides eggerthii) were identified to be highly correlated with the stages of CKD. Paraprevotella, Pseudobutyrivibrio and Collinsella stercoris were superior in discriminating CKD from the controls than the use of urine protein/creatinine ratio, even at early-stage of disease. The performance was further confirmed in a validation cohort comprising 22 controls and 76 peritoneal dialysis patients. Bacterial genera highly correlated with indoxyl sulfate and p-cresyl sulfate levels were identified. Prediction of the functional capabilities of microbial communities showed that microbial genes related to the metabolism of aromatic amino acids (phenylalanine, tyrosine, and tryptophan) were differentially enriched among the control and different CKD stages. Collectively, our results provide solid human evidence of the impact of gut-metabolite-kidney axis on the severity of chronic kidney disease and highlight a usefulness of specific gut microorganisms as possible disease differentiate marker of this global health burden.

The worldwide incidence of hepatocellular carcinoma (HCC), the major histological type of primary liver cancer, is heterogeneous due to the variable prevalence of etiological factors, indicating a correlation of HCC risk with genetic variations among individuals. Among long non-coding RNAs (lncRNAs) located in the chromosome 8q24 loci and involved in the carcinogenesis are colon cancer associated transcript 2 (CCAT2) and cancer susceptibility candidate 8 (CASC8). In this study, the association of CCAT2 and CASC8 gene polymorphisms with the occurrence of HCC was explored between 397 HCC patients and 1195 controls. We found that carriers of rs6983267 GG in CCAT2 were more susceptible to HCC, with the odds ratio (OR) and adjusted odds ratio (AOR) being 1.532 (95% CI, 1.103–2.129; p = 0.011) and 1.627 (95% CI, 1.120–2.265; p = 0.033), respectively. Moreover, for patients stratified by age (under 65), gender (male only), or status of drinking (habitual drinkers), a protective effect of CASC8 rs3843549 on presenting high Child–Pugh scores, metastatic vascular invasion, or large-size tumors was observed in a dominant model. Collectively, our data reveal association of CCAT2 and CASC8 gene polymorphisms with the occurrence and progression of HCC.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, whose diversified occurrence worldwide indicates a connection between genetic variations among individuals and the predisposition to such neoplasms. Mounting evidence has demonstrated that long non-coding RNA (lncRNA) H19 can have both promotive and inhibitory effects on cancer development, revealing a dual role in tumorigenesis. In this study, the link of H19 gene polymorphisms to hepatocarcinogenesis was assessed between 359 HCC patients and 1190 cancer-free subjects. We found that heterozygotes for the minor allele of H19 rs2839698 (T) and rs3741219 (G) were more inclined to develop HCC (OR, 1.291; 95% CI, 1.003–1.661; p = 0.047, and OR, 1.361; 95% CI, 1.054–1.758; p = 0.018, respectively), whereas homozygotes for the polymorphic allele of rs2107425 (TT) were correlated with a decreased risk of HCC (OR, 0.606; 95% CI, 0.410–0.895; p = 0.012). Moreover, patients who bear at least one variant allele (heterozygote or homozygote) of rs3024270 were less prone to develop late-stage tumors (for stage III/IV; OR, 0.566; 95% CI, 0.342–0.937; p = 0.027). In addition, carriers of a particular haplotype of three H19 SNPs tested were more susceptible to HCC. In conclusion, our results indicate an association between H19 gene polymorphisms and the incidence and progression of liver cancer.

Colorectal cancer (CRC) is a multifactorial malignancy, and its high incidence and mortality rate remain a global public health burden. Fibroblast growth factor receptor 4 (FGFR4) is a receptor tyrosine kinase that has been shown to play a key role in cancer development and prognosis via the activation of its downstream oncogenic signaling pathways. The present study aimed to explore the impact of FGFR4 gene polymorphisms on the risk and progression of CRC. Three FGFR4 single-nucleotide polymorphisms (SNPs), including rs1966265, rs351855, and rs7708357, were evaluated in 413 CRC cases and 413 gender- and age-matched cancer-free controls. We did not observe any significant association of three individual SNPs with the risk of CRC between the case and control group. However, while assessing the clinicopathological parameters, patients of rectal cancer possessing at least one minor allele of rs1966265 (AG and GG, AOR, 0.236, p = 0.046) or rs351855 (GA and AA, AOR, 0.191, p = 0.022) were found to develop less metastasis as compared to those who are homozygous for the major allele. Further analyses using the datasets from the Genotype-Tissue Expression (GTEx) Portal and The Cancer Genome Atlas (TCGA) revealed that rs351855 regulated FGFR4 expression in many human tissues, and increased FGFR4 levels were associated with the occurrence, advanced stage, and distal metastasis of colon adenocarcinoma. These data suggest that the amino acid change in combination with altered expression levels of FGFR4 due to genetic polymorphisms may affect CRC progression.

Nasopharyngeal carcinoma (NPC), a disease common in the South-East Asian population, has high lymph node metastatic ability. Melatonin, an endogenously produced substance present in animals, plants, fungi, and bacteria, has oncostatic activity via several mechanisms. The molecular mechanisms involved in melatonin-mediated tumor inhibitory potential are not completely defined. Here, we show that melatonin treatment inhibits TPA-induced cell motility by regulating the matrix metalloproteinase-9 (MMP-9) expression in NPC. We also identified the signaling cascade through which melatonin inhibits MMP-9 expression; this involves melatonin regulating the binding activity of the transcription factor specificity protein-1 (SP-1)-DNA. Our mechanistic analysis further reveals that the c-Jun N-terminal kinase/mitogen-activated protein kinase pathway is involved in the melatonin-mediated tumor suppressor activity. Furthermore, the findings indicate a functional link between melatonin-mediated MMP-9 regulation and tumor suppressing ability and provide new insights into the role of melatonin-induced molecular and epigenetic regulation of tumor growth. Thus, we conclude that melatonin suppresses the motility of NPC by regulating TPA-induced MMP-9 gene expression via inhibiting SP-1-DNA binding ability. The results provide a functional link between melatonin-mediated SP-1 regulation and the antimetastatic actions of melatonin on nasopharyngeal carcinoma.

Melatonin exerts antimetastatic effects on liver and breast cancer and also inhibits matrix metalloproteinase (MMP) activity. However, the detailed impacts and underlying mechanisms of melatonin on oral cancer cell metastasis are still unclear. This study showed that melatonin attenuated the 12-O-tetradecanoylphorbol-13-acetate-induced migration of oral cancer cell lines, HSC-3 and OECM-1. Zymography, quantitative real-time PCR, and Western blotting analyses revealed that melatonin lessened MMP-9 enzyme activity as well as the expression of MMP-9 mRNA and protein. Furthermore, melatonin suppressed the phosphorylation of the ERK1/2 signalling pathway, which dampened MMP-9 gene transcription by affecting the expression of transcriptional coactivators, such as CREB-binding protein (CREBBP) and E1A binding protein p300 (EP300), and decreasing histone acetylation in HSC-3 and OECM-1 cells. Examinations on clinical samples exhibited that MMP-9, CREBBP, and EP300 were significantly increased in oral cancer tissues. Moreover, the relative level of CREBBP was positively correlated with the expression of MMP-9 and EP300. In conclusion, we demonstrated that melatonin inhibits the motility of HSC-3 and OECM-1 cells in vitro through a molecular mechanism that involves attenuation of MMP-9 expression and activity mediated by decreased histone acetylation.

Matrix metalloproteinases (MMPs) are classified in the family of zinc-dependent endopeptidases, which can degrade various components of an extracellular matrix and a basement membrane. Studies have demonstrated that MMPs relate to the development of malignant tumors and induce angiogenesis, resulting in the invasion and metastasis of tumor cells. MMPs are highly expressed in malignant tumors and are related to cancer patients' malignant phenotype and poor prognosis. Therefore, blocking the expression or activity of MMPs may be a promising strategy for cancer treatment.This study aimed to explain the MMP structure, regulatory mechanism, and carcinogenic effect; investigate the matrix metalloproteinase-inhibitors (MMPIs) that are currently used in clinical trials for cancer treatment; and summarize the trial results.Currently, the results of clinical trials that have used MMPIs as anticancer agents are unsatisfactory. However, MMPs remain an attractive target for cancer treatment. For example, development of the specific peptide or antibodies in targeting the hemopexin domain of MMP-2 may be a new therapeutic direction. The design and development of MMPIs that have selectivity will be the primary focus in future studies.