Carcinogenesis最新文献

Previous studies have linked liver diseases to lung cancer (LC) risk; however, few studies evaluated the associations of circulating liver enzyme levels with LC risk. We conducted a study of 353 incident LC cases and 646 matched controls with baseline serum alanine aminotransferase (ALT) and of 548 cases and 1032 matched controls with baseline serum alkaline phosphatase (ALP) nested within the Southern Community Cohort Study. Conditional logistic regression and generalized linear models were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) among all study participants and by stratification of potential effect modifiers. Most participants had clinically normal liver enzyme levels. Higher serum ALT levels were associated with reduced LC risk. Compared with the lowest tertile, participants in the second and third tertiles had OR (95% CI) of 0.74 (0.48-1.14) and 0.47 (0.28-0.78) (Ptrend < .01), respectively. The inverse association was observed in African Americans (AAs) and European Americans, which was especially prominent among men, and was seen in both those diagnosed within [ORT3 versus T1 = 0.41 (0.19-0.88)] and beyond [ORT3 versus T1 = 0.35 (0.17-0.73)] a median follow-up time of 39 months. Higher serum ALP levels were associated with increased LC risk among AA men only [ORT3 versus T1 = 2.01 (1.19-3.39)] (Ptrend < .01). Our results indicate that in a predominantly low-income American population, higher serum ALT levels may be related to lower LC risk. Further studies are warranted to confirm our findings and elucidate the potential underlying biological mechanisms of the associations.

Gastric cancer (GC) is globally recognized as one of the most widespread malignant tumors. As the symptoms of patients with early GC are ambiguous, the majority of patients are given a diagnosis of advanced GC. Therefore, this necessitates the search for new biomarkers to be utilized in the early diagnosis and screening of GC. Enhancer RNA (eRNA) is a non-coding RNA in transcription by enhancers that is tumor-specific and has a critical function in cancer progression. Our research investigates new eRNAs as bio-diagnostic markers for GC. Four eRNAs with good differential expression in GC were screened by TCGA and University of California, Santa Cruz databases. Quantitative real-time PCR was utilized for testing the level of RASSF8-AS1. The diagnostic effect of RASSF8-AS1 was evaluated using the receiver operating characteristic (ROC). Functional experiments were used to detect the ability of RASSF8-AS1 to affect the metastasis and proliferation in GC cells. The expression of RASSF8-AS1 was obviously elevated in both GC tissues and serum, whereas it was decreased in the serum levels of postoperative GC patients. ROC showed that RASSF8-AS1 was more diagnostically efficient than common diagnostic biomarkers for GC and that diagnostic effectiveness could be better than combining them. The findings of in vitro experiments showed that knocking down the level of RASSF8-AS1 clearly suppressed the ability of growth and metastasis in GC cells. Studies have shown that serum RASSF8-AS1 has the potential to contribute to the progression of GC as a biomarker for diagnosis and prognostic monitoring of GC.

CKLF-like MARVEL transmembrane domain-containing (CMTM) proteins play pivotal roles in tumorigenesis and cancer progression across various malignancies. However, their expression profiles and regulatory mechanisms in distinct subtypes of breast cancer remain largely undefined. In this study, we systematically analysed the expression of all nine CMTM family members across major molecular subtypes of breast cancer, including Luminal A, Luminal B, HER2-positive (HER2+), and triple-negative breast cancer (TNBC). Among these, CMTM3 was uniquely downregulated in Luminal B and HER2+ breast cancer cells and functioned as a tumor suppressor. Overexpression of HER2 in normal breast epithelial cell lines led to the phosphorylation of CMTM3. Molecular and biochemical analyses revealed that HER2 overexpression activated the downstream phosphoinositide 3-kinase (PI3K)/protein kinase B (also known as RAC-Alpha Serine/Threonine-Protein Kinase, AKT) signaling pathway in Luminal B and HER2+ breast cancer cells. AKT1 directly phosphorylated CMTM3 at serine 181 (Ser181), a modification that facilitated its recognition and ubiquitination by the E3 ligase HECT domain E3 ubiquitin protein ligase 3 (HECTD3), ultimately targeting CMTM3 for proteasomal degradation. Functional assays demonstrated that either knockdown of HECTD3 or pharmacological inhibition of PI3K/AKT signaling stabilized CMTM3 protein levels. Moreover, reintroducing a nonphosphorylatable CMTM3 mutant (CMTM3S181A) into CMTM3 knockout breast cancer cells resulted in significantly reduced proliferation, colony formation, invasive capacity, and in vivo tumor growth compared with cells expressing wild-type CMTM3 (CMTM3WT). Collectively, these findings reveal a previously unrecognized posttranslational regulatory mechanism of CMTM3 and suggest that targeting the PI3K/AKT-HECTD3-CMTM3 axis may offer a promising therapeutic approach for treating HER2+ breast cancers.

Kidney cancer incidence has increased worldwide in recent decades. While metabolomic studies have shown promise in unveiling mechanisms underlying disease development, few studies have investigated prediagnostic urinary metabolites and kidney cancer risk. We conducted a case-control study nested within the Shanghai Women's and Men's Health Studies to prospectively investigate the association between urinary metabolites and kidney cancer risk to understand its etiology and the underlying biological mechanisms. Two hundred primary kidney cancer cases and their individually matched controls were included. A total of 1301 metabolites were evaluated, and 67 metabolites were found nominally associated with kidney cancer using conditional logistic regression. After backward selection, 11 urine metabolites remained significantly associated with kidney cancer: lipids (e.g. picolinoylglycine, odds ratio [OR]; 95% confidence interval [CI]: 2.01 [1.44, 2.79], and pregnanediol-3-glucuronide, OR; 95% CI: 0.56 [0.39, 0.82]), xenobiotics (e.g. beta-guanidinopropanoate, OR; 95% CI: 1.75 [1.32, 2.32] and 4-vinylphenol sulfate, OR; 95% CI: 0.66 [0.49, 0.90]), and nucleotides (e.g. allantoic acid, OR; 95% CI: 0.71 [0.54, 0.92]). Time lag analysis showed that metabolite-kidney cancer associations were stronger for beta-guanidinopropanoate (OR; 95% CI: 8.22 [1.68, 40.18]) and picolinoylglycine (OR; 95% CI: 6.45 [1.28, 32.43]), but weaker for allantoic acid (OR; 95% CI: 0.87 [0.37, 2.06]) and 3-methylglutarate/2-methylglutarate (OR; 95% CI: 0.62 [0.19, 2.00]) when urinary samples were collected within 3 years between urine sample collection and cancer diagnosis (Pinteraction < .05 for all). Future metabolomics studies with large sample sizes, particularly from multiple ancestry populations, are needed to validate our findings.

Hepatocellular carcinoma (HCC) represents a significant global health challenge, with chemoresistance severely limiting treatment efficacy. This study investigates the role of miRNA-425-5p in exosomes in modulating the tumor microenvironment (TME) and contributing to chemoresistance and immune evasion in HCC. Differentially expressed miRNAs were identified using TaqMan low-density array technology in serum samples from XELOX-resistant and -sensitive HCC patients. miRNA-425-5p expression was validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Exosomes from HCC cell lines were characterized by transmission electron microscopy and nanoparticle tracking analysis. Functional assays, including luciferase reporter assays and flow cytometry, elucidated the mechanisms of miRNA-425-5p. In vivo studies with mouse xenograft models evaluated the impact of miRNA-425-5p on tumor growth and chemosensitivity. miRNA-425-5p was significantly upregulated in the serum of XELOX-resistant HCC patients and correlated with poorer survival outcomes. Exosomes from chemoresistant HCC cells exhibited increased levels of miRNA-425-5p, which, when internalized by CD4+ T cells, promoted regulatory T cell (Treg) expansion by targeting phosphatase and tensin homolog (PTEN). In vivo, miRNA-425-5p overexpression enhanced tumor growth and chemoresistance, while its inhibition reduced tumor size and increased chemosensitivity. These findings indicate that miRNA-425-5p in exosomes plays a crucial role in HCC chemoresistance and immune evasion by modulating the TME and promoting Treg expansion through PTEN targeting. miRNA-425-5p serves as a potential biomarker for predicting chemoresistance and a therapeutic target for overcoming drug resistance in HCC.

Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide, with roughly 41% of CRC cases harboring a KRAS mutation. Acquired resistance to KRAS-targeted treatments has occurred with mechanisms including increased HER family expression among other receptor tyrosine kinases. HER3, a member of the HER family that is kinase impaired, has been shown to be a resistance mechanism upon inhibition of the HER family and downstream targets, including RAS/MEK/ERK and PI3K/AKT. We find that KRAS mutations tend to co-occur with HER3 alterations in a large panel of cancers and in CRCs. Our results show that both total and activated HER3 levels increase in CRC patient-derived organoids and cell lines after treatment with KRASG12D targeted agents, indicating that HER3 could be a potential adaptive response mechanism to KRAS-targeted therapy. Further, we found that genetic knock-down of KRAS and HER3 resulted in a reduction in the growth of CRC cells compared to a single knockdown of either KRAS or HER3. We observed that kinase-impaired HER3 binding partners, as assessed by immunoprecipitation, is cell dependent with EGFR binding HER3 in one cell line. After co-treating CRC cells with pan-HER inhibitors in combination with MRTX1133, a KRASG12D inhibitor, synergistic and additive effects in the reduction in cell growth were observed. Finally, we found that co-targeting KRASG12D mutant cells with a KRASG12D inhibitor and a HER3 antibody-drug conjugate further reduced cell viability. We posit that co-targeting both KRASG12D and HER3, whether directly or indirectly, is a potential therapeutic strategy in CRC patients.

Lung cancer is the leading cause of cancer mortality. To investigate genetic determinants for prognosis among patients diagnosed with early-stage non-small cell lung cancer (NSCLC), we conducted the first large-scale genome-wide association prognostic study using data from the International Lung Cancer Consortium (ILCCO) through a two-phase analysis. Phase 1 includes the discovery of genome-wide association studies analysis using a multivariable Cox PH model on 3428 NSCLC patients of European ancestry from 10 ILCCO participating studies to identify genetic variants associated with overall survival and validation analysis for genome-wide significant variants (P-value ≤5 × 10-8) using the Cancer Genome Atlas (TCGA). Phase 2 aims to identify causal variants using functional analyses of genome-wide significant and suggestive variants (P-value ≤1 × 10-5), including variant-epigenetic functional annotation (FAVOR), CHIP-seq data, variant-gene expression association, and colocalization analysis. We identified two significant variants; of those, a locus at 9q21.31 (rs117979484) was significant at the genome-wide level (P = 3.67 × 10-8) and validated in TCGA (P = 0.03). Three suggestive variants were found to have a putative epigenetic function: intronic variants rs149281784 (BCL7B gene) and rs148031766 (POM121 gene) both located at 7q11.23 and in moderate linkage disequilibrium with each other; and variant rs2471630 (SRCIN1 gene; 17q12). Specifically, variants rs149281784 and rs148031766 have potential regulatory roles in the transcriptional activation of the BCL7B gene and POM121 gene. Exploratory survival analyses in the squamous cell carcinomas subgroup also identified a significant variant, rs138467404 (GRHL-2 gene; 8q22.3) at a genome-wide level (P = 4.75 × 10-8) and validated by TCGA (P = 0.02). These new findings indicate potential novel pathways associated with early-stage NSCLC prognosis. Future research may validate additional genome-wide suggestive variants as being relevant for lung cancer outcomes.

Long-chain noncoding RNA (LncRNA) MEG3 significantly influences tumor microenvironment (TME) dynamics and macrophage polarization. However, its specific involvement in prostate cancer (PCa) progression remains unclear. MEG3 exhibited low expression in PCa, and immune infiltration analysis revealed a positive association with M1 macrophages infiltration and a negative association with M2 macrophages infiltration. Immunohistochemical analysis demonstrated increased MEG3 levels, corresponding with upregulated INOS (an M1 marker) and downregulated CD163 (an M2 marker). MEG3 expression was markedly elevated in LPS-induced M1 macrophages and notably reduced in IL-4-induced M2 macrophages. The overexpression of MEG3 significantly enhanced M1 macrophages polarization while suppressing M2 macrophages polarization. Using an online database and a dual luciferase reporter assay, miR-148a-3p was identified as a downstream target of MEG3. Reduced miR-148a-3p expression was observed in LPS-induced M1 macrophages, while an increase was noted in IL-4-induced M2 macrophages. Moreover, MEG3 overexpression's impact on macrophage polarization was nullified following miR-148a-3p mimic transfection. ARRDC3 was validated as a downstream target of miR-148a-3p. The upregulation of ARRDC3 triggered by MEG3 overexpression was effectively suppressed by miR-148a-3p mimics. Additionally, Knockdown of ARRDC3 effectively counteracted the MEG3 overexpression-induced increase in M1 macrophages polarization while simultaneously mitigating the reduction in M2 macrophages polarization. Collectively, MEG3 exhibits reduced expression in PCa and correlates with macrophage infiltration and polarization. Specifically, it drives M1 macrophages polarization while suppressing M2 macrophages polarization via the miR-148a-3p/ARRDC3 axis, thereby impeding tumor immune evasion and restricting PCa progression.