Comprehensive profiling of DNA methylation in Korean patients with colorectal cancer.

Alterations in DNA methylation play an important pathophysiological role in the development and progression of colorectal cancer. We comprehensively profiled DNA methylation alterations in 165 Korean patients with colorectal cancer (CRC), and conducted an in-depth investigation of cancer-specific methylation patterns. Our analysis of the tumor samples revealed a significant presence of hypomethylated probes, primarily within the gene body regions; few hypermethylated sites were observed, which were mostly enriched in promoter-like and CpG island regions. The CpG Island Methylator PhenotypeHigh (CIMP-H) exhibited notable enrichment of microsatellite instability-high (MSI-H). Additionally, our findings indicated a significant correlation between methylation of the MLH1 gene and MSI-H status. Furthermore, we found that the CIMP-H had a higher tendency to affect the right-side of the colon tissues and was slightly more prevalent among older patients. Through our methylome profile analysis, we successfully verified the thylation patterns and clinical characteristics of Korean patients with CRC. This valuable dataset lays a strong foundation for exploring novel molecular insights and potential therapeutic targets for the treatment of CRC. [BMB Reports 2024; 57(2): 110-115].

Cdc7 kinase is a predictor of survival and a novel therapeutic target in epithelial ovarian carcinoma.

PURPOSE: There is a lack of prognostic and predictive biomarkers in epithelial ovarian carcinoma, and the targeting of oncogenic signaling pathways has had limited impact on patient survival in this highly heterogeneous disease. The origin licensing machinery, which renders chromosomes competent for DNA replication, acts as a convergence point for upstream signaling pathways. We tested the hypothesis that Cdc7 kinase, a core component of the licensing machinery, is predictive of clinical outcome and may constitute a novel therapeutic target in epithelial ovarian carcinoma. EXPERIMENTAL DESIGN: A total of 143 cases of ovarian cancer and 5 cases of normal ovary were analyzed for Cdc7 protein expression dynamics and clinicopathologic features. To assess the therapeutic potential of Cdc7, expression was down-regulated by RNA interference in SKOV-3 and Caov-3 ovarian cancer cells. RESULTS: Increased Cdc7 protein levels were significantly associated with arrested tumor differentiation (P = 0.004), advanced clinical stage (P = 0.01), genomic instability (P < 0.001), and accelerated cell cycle progression. Multivariate analysis shows that Cdc7 predicts disease-free survival independent of patient age, tumor grade and stage (hazard ratio, 2.03; confidence interval, 1.53-2.68; P < 0.001), with the hazard ratio for relapse increasing to 10.90 (confidence interval, 4.07-29.17) for the stages 3 to 4/upper Cdc7 tertile group relative to stages 1 to 2/lower Cdc7 tertile tumors. In SKOV-3 and Caov-3 cells, Cdc7 siRNA knockdown triggered high levels of apoptosis, whereas untransformed cells arrest in G(1) phase and remain viable. CONCLUSIONS: Our findings show that Cdc7 kinase predicts survival and is a potent anticancer target in epithelial ovarian carcinoma, highlighting its potential as a predictor of susceptibility to small molecule kinase inhibitors currently in development.

Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer.

Immunotherapy for metastatic colorectal cancer is effective only for mismatch repair-deficient tumors with high microsatellite instability that demonstrate immune infiltration, suggesting that tumor cells can determine their immune microenvironment. To understand this cross-talk, we analyzed the transcriptome of 91,103 unsorted single cells from 23 Korean and 6 Belgian patients. Cancer cells displayed transcriptional features reminiscent of normal differentiation programs, and genetic alterations that apparently fostered immunosuppressive microenvironments directed by regulatory T cells, myofibroblasts and myeloid cells. Intercellular network reconstruction supported the association between cancer cell signatures and specific stromal or immune cell populations. Our collective view of the cellular landscape and intercellular interactions in colorectal cancer provide mechanistic information for the design of efficient immuno-oncology treatment strategies.

Angiogenesis induced by autologous whole bone marrow stem cells transplantation.

BACKGROUND AND OBJECTIVES: It has been presumed that unknown cells and growth factors in bone marrow might promote angiogenesis, so angiogenesis effect could be enhanced by autologous whole bone marrow (WBM) stem cell transplantation. We compared capillary ratio induced by autologous WBM and bone marrow-mononuclear cells (BM-MNCs) to evaluate the anigiogenic effect of auotologous WBM. In addition, the combined effect of WBM transplantation and granulocyte colony-stimulating factor (G-CSF) injection was examined in an ischemic canine model. METHODS AND RESULTS: After creating ischemic limb model, autologous WBM and isolated BM-MNCs were transplanted into the ischemic muscle. In other experiments, autologous WBM with recombinant human G-CSF (rhG-CSF) and autologous WBM without rhG-CSF were transplanted into the ischemic muscle. In this study, normal saline was injected into the contralateral sites in each ischemic model as a control group. After 8 weeks of transplantation, angiography and muscle harvest were performed, and then the anigiographic findings and capillary density, as assessed by immunohistochemical staining, were investigated and analyzed. In comparison with the control group, BM-MNCs and WBM transplantation groups showed higher ratios of the capillary density (1.5±0.01 times, p<0.001 and 1.6±0.15 times, p=0.005, respectively). Between the BM-MNCs and WBM transplantation groups, the capillary ratio was 1.2 folds higher in the WBM group than that in the BM-MNCs group, but there was no significantly different (p=0.116). The angiogensis ratios of both the WBM without G-CSF group and the WBM with G-CSF groups were higher (1.6±0.15 times, p=0.004 and 1.8 ±0.01 times, p=0.005, respectively) than that of the control groups. In comparison with the WBM without G-CSF group, the WBM with G-CSF transplantation group revealed a 1.1 folds higher angiogenesis ratio, but there was no statistically significant difference (p=0.095). CONCLUSIONS: Autologous WBM transplantation is a simpler method and it is not inferior for inducing therapeutic angiogenesis as compared with isolated BM-MNCs transplantation. In addition to autologous WBM transplantation, intravenous G-CSF injection enhances the angiogenic effect of autologous WBM in an ischemic limb.