Background Both gastric and colorectal cancers (CRC) are the most frequently occurring malignancies worldwide with the overall survival of these patients remains unsatisfied. Identification of tumor suppressor genes (TSG) silenced by promoter CpG methylation uncovers mechanisms of tumorigenesis and identifies new epigenetic biomarkers for early cancer detection and prognosis assessment. Cystathionine-beta-synthase (CBS) functions in the folate metabolism pathway, which is intricately linked to methylation of genomic DNA. Dysregulation of DNA methylation contributes substantially to cancer development. Methodology/Principal Findings To identify potential TSGs silenced by aberrant promoter methylation in CRC, we analyzed tumor and adjacent tissues from CRC cases using the Illumina Human Methylation45 BeadChip. We identified hypermethylation of the CBS gene in CRC samples, compared to adjacent tissues. Methylation and decreased mRNA expression of CBS were detected in most CRC cell lines by methylation-specific PCR and semiquantitative RT-PCR, as well as in gastric cancer. Treatment with 5-aza-2'-deoxycytidine and/or trichostatin A reversed methylation and restored CBS mRNA expression indicating a direct effect. Aberrant methylation was further detected in 31% of primary CRCs (29 of 96) and 55% of gastric tumors (11 of 20). In contrast, methylation was seldom found in normal tissues adjacent to the tumor. CBS methylation was associated with KRAS mutations in primary CRCs (P = 0.04, by χ2-test). However, no association was found between CBS methylation or KRAS mutations with cancer relapse/metastasis in Stage II CRC patients. Conclusion A novel finding from this study is that the folate metabolism enzyme CBS mRNA levels are frequently downregulated through CpG methylation of the CBS gene in gastric cancer and CRC, suggesting that CBS functions as a tumor suppressor gene. These findings warrant further study of CBS as an epigenetic biomarker for molecular diagnosis of gastrointestinal cancers.
Abstract Tertiary lymphoid structures (TLSs) have been associated with favorable immunotherapy responses and prognosis in various cancers. Despite their significance, their quantification using multiplex immunohistochemistry (mIHC) staining of T and B lymphocytes remains labor-intensive, limiting its clinical utility. To address this challenge, we curated a dataset from matched mIHC and H&E whole-slide images (WSIs) and developed a deep learning model for automated segmentation of TLSs. The model achieved Dice coefficients of 0.91 on the internal test set and 0.866 on the external validation set, along with intersection over union (IoU) scores of 0.819 and 0.787, respectively. The TLS ratio, defined as the segmented TLS area over the total tissue area, correlated with B lymphocyte levels and the expression of CXCL13 , a chemokine associated with TLS formation, in 6140 patients spanning 16 tumor types from The Cancer Genome Atlas (TCGA). The prognostic models for overall survival indicated that the inclusion of the TLS ratio with TNM staging significantly enhanced the models’ discriminative ability, outperforming the traditional models that solely incorporated TNM staging, in 10 out of 15 TCGA tumor types. Furthermore, when applied to biopsied treatment-naïve tumor samples, higher TLS ratios predicted a positive immunotherapy response across multiple cohorts, including specific therapies for esophageal squamous cell carcinoma, non-small cell lung cancer, and stomach adenocarcinoma. In conclusion, our deep learning-based approach offers an automated and reproducible method for TLS segmentation and quantification, highlighting its potential in predicting immunotherapy response and informing cancer prognosis.
Background Activation of PRR11 contributes to the progression of lung cancer and is related to its methylation status. However, the regulatory mechanism of luteolin-zinc (Lu-Zn) on PRR11 methylation-mediated lung cancer progression under hypoxic conditions remains to be explored.. Purpose This study aims to investigate the inhibitory effect of Lu-Zn on lung cancer cells, its regulation of ferroptosis, and the role of PRR11 in lung cancer progression under hypoxia. Methods In vitro experiments were conducted to evaluate the effect of Lu-Zn on lung cancer cells, focusing on its impact on invasion, migration, and ferroptosis. The expression levels of PRR11, its methylation status, and microRNA-6769b-3p (miR-6769b-3p) were also analyzed. Results Under hypoxic conditions, Lu-Zn significantly inhibited the invasion and migration abilities of lung cancer cells and promoted ferroptosis. Additionally, Lu-Zn reversed the pro-cancer effects induced by PRR11. At the molecular level, Lu-Zn promoted the methylation of PRR11 and regulated miR-6769b-3p. Conclusion Our study demonstrates that Lu-Zn enhances the methylation of PRR11 and reduces its expression under hypoxic conditions through miR-6769b-3p. This leads to inhibition of the downstream PI3K/AKT/mTOR signaling pathway, promoting ferroptosis and exerting anti-lung cancer effects.
It remains unclear that how tumor immune micro-environment will change following neoadjuvant chemotherapy (NACT) in locally advanced gastric cancer (LAGC). In this study, we aimed to characterize the changes in tumor-infiltrating immune cells and checkpoint molecules following NACT and investigate the prognostic value of these changes in LAGC. Paired tumor samples (pre-NACT and post-NACT) of 60 patients were retrospectively identified and analyzed by multiplex immunohistochemistry with a panel including CD4, CD8, FOXP3, PD-1, PD-L1, and TIM3. Following NACT, the overall median expression levels of CD4, CD8, PD1, PD-L1 and TIM3 were significantly increased (P = 0.008 for PD-L1 and P < 0.001 for all the other markers), while the median FOXP3 expression level remained stable (P = 0.120). Individually, the majority of patients presented increased expression of the markers, while 8.5%, 11.9%, 16.9%, 25.4%, 22.0% and 42.2% of patients had decreased expression of CD4, CD8, PD-1, PD-L1, TIM3 and FOXP3, respectively. Changes in expression between baseline and post-NACT of TIM3, PD-1, and PD-L1 showed strongly positive pairwise correlations with each other (P < 0.001). Multivariate analysis demonstrated that high upregulation levels of CD8 (HR = 0.73, P = 0.028), PD-1 (HR = 0.76, P = 0.027), and PD-L1 (HR = 0.67, P = 0.038) following NACT were beneficial prognostic factors of OS. NACT increase the expression of multiple checkpoint molecules and infiltration of CD4+, CD8+ immune cells in LAGC with the levels of changes in checkpoint molecules positively related with each other. This may raise the possibility of applying immunotherapy with chemotherapy or even dual checkpoint inhibitors in LAGC.
<p>Supplementary Table 3. The immune-related pathways that were enriched in TERT methylation high group versus TERT methylation low group using GSEA analysis.</p>
Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on a few hotspot integrations. However, the oncogenic role of the other HBV integrations remains unclear. This study aimed to elucidate HBV integration-induced tumourigenesis further.
Abstract Objective Recent studies have reported increased mortality for right‐sided colon cancers; however, the results are conflicting for different stage tumors. We examined the differences in clinicopathology between right‐ and left‐sided colon cancers and the relationships between colon cancer location (right‐ and left‐side) and 5‐year disease‐free survival (DFS) and overall survival (OS). Methods We identified patients from 2005 to 2008 with stage II/III colon cancer who underwent surgery for curative intent. We explored the impact of the tumor location on the postoperative DFS and OS using univariate and multivariate analyses. Results Of 627 patients, 50.6% (317/627) had right‐sided colon cancer. These patients were more likely to have weight loss, second primary tumor, elevated preoperative carbohydrate antigen 19‐9 (CA19‐9), increased incidence of non‐adenocarcinoma, more poorly differentiated tumors, vascular invasion, defective mismatch repair, and a lighter smoking history ( P < 0.05). Right‐sided colon cancer had a higher recurrence incidence compared with left‐sided cancer (30.6% vs. 23.2%, P = 0.037), particularly with multiple metastatic sites in the first recurrence (17.5% vs. 5.6%, P = 0.020). Kaplan–Meier survival curves demonstrated a significant difference in the 5‐year DFS rate between right‐ and left‐sided cancers across all stages (68.1% vs. 75.2%, P = 0.043). However, there was no significant difference in the 5‐year OS rate between the two groups (73.8% vs. 79.0%, P = 0.103). Subgroup analysis demonstrated that patients with left‐sided colon cancer had a significantly better 5‐year DFS and OS rates compared with those with right‐sided disease at stage III (64.3% vs. 46.8%, P = 0.002; 69.5% vs. 53.5%, P = 0.006, respectively); there were no significant differences in the 5‐year DFS and OS rates at stage II (85.2% vs. 85.9%, P = 0.819; 89.8% vs. 88.5%, P = 0.803, respectively). Adjusted Cox regression analysis showed no significant differences in the 5‐year OS and DFS rates for stage II [hazard ratio ( HR ) = 1.203, 95% confidence interval ( CI ): 0.605–2.391, P = 0.598; HR = 0.980, 95% CI : 0.542–1.774, P = 0.948, respectively] or all stages combined ( HR = 0.867, 95% CI : 0.613–1.227, P = 0.421; HR = 0.832, 95% CI : 0.606–1.142, P = 0.255, respectively). However, stage III left‐sided cancer had higher 5‐year OS and DFS rates ( HR = 0.626, 95% CI : 0.414–0.948, P = 0.027; HR = 0.630, 95% CI : 0.428–0.926, P = 0.019, respectively). Conclusion We found that right‐ and left‐sided colon cancers had significantly different clinicopathological characteristics. Right‐sided colon cancer had a higher incidence of recurrence than left‐sided disease. Patients with stage III right‐sided colon cancer had a worse prognosis compared with those with stage III left‐sided colon cancer.
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