Molecular Carcinogenesis最新文献

We conducted the first genome-wide association study (GWAS) of colorectal cancer (CRC) in Taiwan with 5342 cases and 61,015 controls. Ninety-two SNPs in three genomic regions reached genome-wide significance (p < 5 × 10^-8). The lead SNPs in these three regions were: rs12778523 (OR = 1.18, 95% CI, 1.15-1.23, p = 4.51 × 10^-13), an intergenic SNP between RNA5SP299 and LINC02676 at chromosome 10p14; rs647161 (OR = 1.14, 95% CI, 1.09-1.19, p = 2.21 × 10^-9), an intronic SNP in PITX1 at 5q31.1, and rs10427139 (OR = 1.20, 95% CI, 1.14-1.28, p = 3.62 × 10^-9), an intronic SNP in GPATCH1 at 19q13.1. We further validated CRC susceptibility SNPs previously identified through GWAS in other populations. A total of 61 CRC susceptibility SNPs were confirmed in Taiwanese. The top validated putative CRC susceptibility genes included: POU2AF2, HAO1, LAMC1, EIF3H, BMP2, ZMIZ1, BMP4, POLD3, CDKN1A, PREX1, CDKN2B, CDH1, and LRIG1. The top enriched pathways included TGF-β signaling, BMP signaling, extracellular matrix organization, DNA repair, and cell cycle control. We could not validate SNPs in HLA-G at 6p22.1 and in NOTCH4 at 6p21.32. We generated a weighted genetic risk score (GRS) using the 61 SNPs and constructed receiver operating characteristic (ROC) curves using the GRS to predict CRC. The area under the ROC curve (AUC) was 0.589 for GRS alone and 0.645 for GRS, sex, and age. These susceptibility SNPs and genes provide important insights into the molecular mechanisms of CRC development and help identify high-risk individuals for CRC in Taiwan.

The reverse transcriptase subunit of telomerase, TERT, is frequently activated in high-grade dysplasia and invasive cancers of the uterine cervix. Telomerase activation through hypomethylation of the TERT promoter holds promise as a biomarker for cervical cancer progression, however, specific CpG sites involved in cervical cancer risk remain to be fully defined. A recent genome-wide association study on cervical cancer identified genetic polymorphisms at 5p13.33 (close to TERT-CLPTM1L) but the underlying mechanisms are undetermined. We investigated 529 CpG sites within the TERT promoter region and 3 CpG islands nearby, and 21 CpG sites within CLPTM1L in 190 bisulfite-converted cervical tumor DNA samples from BioRAIDs (NCT02428842). We identified eight CpG sites within TERT intron 2 where methylation was significantly associated with the genotypes of cervical cancer risk variants rs27070 and rs459961 in cervical tumors after multiple testing correction (p < 9.4 × 10E-5). Hypermethylation at chr5:1289663 correlated with decreased TERT mRNA levels. In an independent series of 188 normal or dysplastic cervical tissues, rare alleles of rs27070 and rs459961 were associated with low basal CLPTM1L levels and with the absence of TERT mRNA in HPV-negative samples, consistent with their proposed role as protective variants for cervical cancer. HPV infection was associated with increased CLPTM1L and TERT levels. Collectively, our results provide a link between cervical cancer risk variants, methylation, and gene expression and implicate both TERT and CLPTM1L as genes modulated by genomic background and HPV infection during cervical cancer development.

We hypothesized that cell energy metabolic profiles correlate with normal, dysplastic, and tumor cell/tissue statuses and may be indicators of aggressiveness in oral squamous cell carcinoma (OSCC) cells. The energy-related proteins that were differentially expressed in human OSCC fragments (n = 3) and their adjacent epithelial tissue (TAE) were verified using mass spectrometry (MS). Immunohistochemistry for 4-hydroxynonenal (4-HNE) was performed to evaluate the oxidative stress patterns in OSCC (n = 10), epithelial dysplasia (n = 9), and normal epithelial (n = 4) biopsies. The metabolic energy profile of OSCC aggressiveness was investigated in human OSCC cell lines with different levels of epithelial-mesenchymal transition proteins. The genes associated with the proteins found by MS in this study were analyzed using survival analysis (OS), whereas the genes associated with a poorer prognosis were analyzed using context-specific expression, Gene Ontology (GO) and Cancer Hallmarks for function enrichment analysis. The rationale for all experimental approach was to investigate whether the variation in energy metabolism profile accompanies the different phenotypes (from epithelial to mesenchymal) during the epithelial-mesenchymal transition. All OSCC fragments exhibited an increase in glycolysis-related proteins and a decrease in mitochondrial activity compared to the TAE region (p < 0.05), probably due to the downregulation of pyruvate dehydrogenase and antioxidant proteins. Additionally, the OSCC cell lines with a mesenchymal profile (SCC4, SCC9, and SCC25) had a lower mitochondrial mass and membrane potential and generated lower levels of reactive oxygen and nitrogen species than the TAE region. When we analyzed 4-HNE, the reactive species levels were increased in the epithelial regions of OSCC and potentially malignant lesions. A decrease in the levels of 4-HNE/reactive species was observed in the connective tissue underlying the dysplastic regions and the OSCC invasion zone. Based on this scenario, aggressive OSCC is associated with high glycolytic and oxidative metabolism and low mitochondrial and antioxidant activities, which vary according to the differentiation level of the tumor cells and the stage of carcinogenesis.

Thyroid cancer (TC) is the prevailing malignancy that impacts the endocrine system, accounting for 1% of all recently diagnosed malignancies in humans. The incidence of TC has been continuously increasing, which can be attributed to advancements in clinical diagnostic technology. However, the mechanisms behind the development of TC are still not well understood. TC is classified into four pathological forms: medullary thyroid cancer, papillary thyroid cancer (PTC), follicular thyroid cancer, and poorly differentiated TC. PTC constitutes more than 80% of all TC cases globally. Current research indicates that complex genetic and cellular processes could be responsible for the growth and spread of TC. Next-generation sequencing (RNA-seq) of 79 PTC samples and their corresponding normal thyroid tissues was performed to investigate the molecular mechanisms of PTC. An analysis of RNA-seq data from a local cohort from The Cancer Genome Atlas (TCGA) revealed that, compared with normal tissues, PTC tissues presented elevated FAM20C expression levels. In vitro, the function of FAM20C was validated with small interfering RNA (siRNA). Gene set enrichment analysis (GSEA) revealed the pathways influenced by FAM20C. A western blot experiment was used to investigate protein expression levels associated with epithelial‒mesenchymal transition (EMT). In conclusion, by regulating EMT, FAM20C facilitates PTC cell proliferation and metastasis.

Cancer stem cells (CSCs) are involved in the regulation of tumor initiation, progression, recurrence, and chemoresistance. However, the role of microRNAs (miRNAs) in liver CSCs has not been fully understood. Here we show that miR-2117 is downregulated in liver CSCs and predicts the poor prognosis of hepatocellular carcinoma (HCC) patients. Biofunction studies found that knockdown miR-2117 facilitates liver CSCs self-renewal and tumorigenesis. Conversely, forced miR-2117 expression suppresses liver CSCs self-renewal and tumorigenesis. Mechanistically, we find that transcription factor SOX2 is required for miR-2117-mediated liver CSCs expansion. The correlation between miR-2117 and SOX2 was confirmed in human HCC tissues. More importantly, miR-2117 overexpression HCC cells are more sensitive to CDDP treatment. Analysis of patients' cohort further demonstrates that miR-2117 may predict transcatheter arterial chemoembolization benefits in HCC patients. Our findings revealed the crucial role of miR-2117 in liver CSCs expansion, rendering miR-2117 as an optimal therapeutic target for HCC.

Previous studies have indicated that specific CpG sites may be linked to the risk of prostate cancer (PCa) by regulating the expression of PCa target genes. However, most existing studies aim to identify DNA methylation (DNAm) biomarkers through blood tissue genetic instruments, which impedes the identification of relevant biomarkers in prostate tissue. To identify PCa risk-associated CpG sites in prostate tissue, we established genetic prediction models of DNAm levels using data from normal prostate samples in the GTEx (N = 108) and assessed associations between genetically predicted DNAm in prostate and PCa risk by studying 122,188 cases and 604,640 controls. We observed significant associations for 3879 CpG sites, including 926 at novel genomic loci. Among them, DNAm levels of 80 CpG sites located at novel loci are significantly associated with expression levels of 45 neighboring genes in normal prostate tissue. Of these genes, 11 further exhibit significant associations with PCa risk for their predicted expression levels in prostate tissue. Intriguingly, a total of 31 CpG sites demonstrate consistent association patterns across the methylation-gene expression-PCa risk pathway. Our findings suggest that specific CpG sites may be related to PCa risk by modulating the expression of nearby target genes.

Zinc finger protein 480 (ZNF480) may interact with lysine-specific demethylase 1 (LSD1), which is highly expressed in many malignant tumors; however, ZNF480 expression has not previously been investigated in breast cancer. Therefore, we explored the expression and molecular mechanisms of ZNF480 in breast cancer. According to public databases and immunohistochemical staining analysis, ZNF480 is highly expressed in the tissue of patients with breast cancer, and ZNF480 expression is positively correlated with advanced TNM stage (p = 0.036), lymph node metastasis (p = 0.012), and poor prognosis (p = 0.005). ZNF480 overexpression enhances breast cancer cell proliferation, migration, and stemness by activating AKT-GSK3β-Snail signaling both in vitro and in vivo. Moreover, ZNF480 binds to LSD1 through its KRAB domain, thereby activating AKT signaling. Mass spectrometry and co-immunoprecipitation revealed that ZNF480 abrogates ubiquitination degradation and subsequently stabilizes LSD1 through competitive binding with TRIM28. Ipragliflozin was identified as a small-molecule inhibitor of ZNF480 and LSD1 interaction that may block breast cancer progression. Moreover, ZNF480 expression was significantly higher in treatment-resistant patients than in treatment-sensitive patients. Thus, ipragliflozin may neutralize neoadjuvant chemotherapy resistance induced by ZNF480 overexpression. Overall, elevated ZNF480 expression is positively associated with poor patient outcomes. Mechanistically, ZNF480 accelerates proliferation and neoadjuvant chemotherapy resistance in breast cancer cells via the AKT-GSK3β-Snail pathway by interacting with and stabilizing LSD1 in a competitive manner within TRIM28. This research has implications for developing targeted drugs against chemotherapy resistance in breast cancer.

Women with germline BRCA1 mutations face an increased risk of developing breast and ovarian cancers. BARD1 (BRCA1 associated RING domain 1) is an essential heterodimeric partner of BRCA1, and mutations in BARD1 are also associated with these cancers. While BARD1 mutations are recognized for their cancer susceptibility, the exact roles of numerous BARD1 missense mutations remain unclear. In this study, we conducted functional assays to assess the homology-directed DNA repair (HDR) activity of all BARD1 missense substitutions identified in 55 breast and ovarian cancer samples, using the real-world data from the COSMIC and cBioPortal databases. Seven BARD1 variants (V85M, P187A, G491R, R565C, P669L, T719R, and Q730L) were confirmed to impair DNA damage repair. Furthermore, cells harboring these BARD1 variants exhibited increased sensitivity to the chemotherapeutic drugs, cisplatin, and olaparib, compared to cells expressing wild-type BARD1. These findings collectively suggest that these seven missense BARD1 variants are likely pathogenic and may respond well to cisplatin-olaparib combination therapy. This study not only enhances our understanding of BARD1's role in DNA damage repair but also offers valuable insights into predicting therapy responses in patients with specific BARD1 missense mutations.

Delta-like homolog 2 (DLK2) plays a crucial role in adipogenesis, chondrogenic differentiation, and the progression of certain cancers. However, the key roles of DLK2 underlying the progression of hepatocellular carcinoma (HCC) remain ambiguous. In the current study, we demonstrate that DLK2 is upregulated in HCC, significantly correlated with clinicopathological variables and serves as an independent diagnostic marker. Functional assays reveal that DLK2 facilitates malignant progression of HCC in vitro and in vivo models. Mechanistically, DLK2 binds to EGFR resulting in its auto-phosphorylation, which activates NF-κB pathway leading to P65-dependent transcriptional upregulation of PKM2. Furthermore, that elevates both enzyme-dependent and -independent activities of PKM2 contributing to cancer proliferation and metastasis. In summary, our findings demonstrate a novel pro-tumoral role and mechanism of DLK2 in the regulation of HCC malignant progression, suggesting its potential as a clinical diagnostic marker and therapeutic target.

Cutaneous squamous cell carcinoma (cSCC) is an increasingly common malignancy of the skin and the leading cause of death from skin cancer in adults over the age of 85. Fibroblast growth factor receptor 2 (FGFR2) has been identified as an important effector of signaling pathways that lead to the growth and development of cSCC. In recent years, there have been numerous studies evaluating the role FGFR2 plays in multiple cancers, its contribution to resistance to anticancer therapy, and new drugs that may be used to inhibit FGFR2. This review will provide an overview of our current understanding of FGFR2 and potential mechanisms in which we can target FGFR2 in cSCC. The goals of this review are the following: (1) to highlight our current knowledge of the role of FGFR2 in healthy skin and contrast this with its role in the development of cancer; (2) to further explain the specific molecular mechanisms that FGFR2 uses to promote tumorigenesis; (3) to describe how FGFR2 contributes to more invasive disease; (4) to describe its immunosuppressive effects in skin; and (5) to evaluate its effect on current anticancer therapy and discuss therapies on the horizon to target FGFR2 related malignancy.