Establishment of apoptotic regulatory network for genetic markers of colorectal cancer and optimal selection of traditional Chinese medicine target

The paper aimed to screen out genetic markers applicable to early diagnosis for colorectal cancer and establish apoptotic regulatory network model for colorectal cancer, and to analyze the current situation of traditional Chinese medicine (TCM) target, thereby providing theoretical evidence for early diagnosis and targeted therapy of colorectal cancer. Taking databases including CNKI, VIP, Wanfang data, Pub Med, and MEDLINE as main sources of literature retrieval, literatures associated with genetic markers that are applied to early diagnosis of colorectal cancer were searched and performed comprehensive and quantitative analysis by Meta analysis, hence screening genetic markers used in early diagnosis of colorectal cancer. KEGG analysis was employed to establish apoptotic regulatory network model based on screened genetic markers, and optimization was conducted on TCM targets. Through Meta analysis, seven genetic markers were screened out, including WWOX, K-ras, COX-2, P53, APC, DCC and PTEN, among which DCC has the highest diagnostic efficiency. Apoptotic regulatory network was built by KEGG analysis. Currently, it was reported that TCM has regulatory function on gene locus in apoptotic regulatory network. The apoptotic regulatory model of colorectal cancer established in this study provides theoretical evidence for early diagnosis and TCM targeted therapy of colorectal cancer in clinic.     

Oxidative stress induced autophagy in cancer associated fibroblast enhances proliferation and metabolism of colorectal cancer cells

Tumors are comprised of malignant cancer cells and stromal cells which constitute the tumor microenvironment (TME). Previous studies have shown that cancer associated fibroblast (CAF) in TME is an important promoter of tumor initiation and progression. However, the underlying molecular mechanisms by which CAFs influence the growth of colorectal cancer cells (CRCs) have not been clearly elucidated. In this study, by using a non-contact co-culture system between human colorectal fibroblasts (CCD-18-co) and CRCs (LoVo, SW480, and SW620), we found that fibroblasts existing in tumor microenvironment positively influenced the metabolism of colorectal cancer cells, through its autophagy and oxidative stress pathway which were initially induced by neighboring tumor cells. Therefore, our data provided a novel possibility to develop fibroblasts as a potential target to treat CRC.     

Small-molecule CB002 restores p53 pathway signaling and represses colorectal cancer cell growth

Much effort is currently focused on the p53 pathway. p53 is a key tumor suppressor, which is mutated or lost in many human cancers. Restoration of the p53 pathway holds the potential to induce selective cell death in tumor cells without harming normal cells that have intact p53 pathways. Most tumor cells express mutated p53 or suppress p53 by overexpression of MDM2. In this study, a compound referred to as CB002 with one closely related compound from the Chembridge library were evaluated for tumor cytotoxicity without affecting normal cells by restoration of the p53 pathway. A decrease of mutant p53 protein expression, restoration of inactivated p53, or some activation of p73 are candidate mechanisms this agent could cause tumor cell apoptosis and growth arrest. We further show that CB002 activates p53 pathway signaling in part via p73 in p53 mutant cancer cell lines. However, it is important to note that we have not established a role for p73 in the anti-tumor effect of CB002 or R1. CB002 causes tumor cell death with synergistic effects with traditional chemotherapeutics CPT-11 and 5-FU.     

预警症状对结直肠癌的诊断效能研究

目的:明确预警症状(腹部包块、便秘、排便习惯改变、腹泻、肛周异物感、长期腹痛、便血或肛门出血)对结直肠癌的诊断效能。方法:收集我院2016年1月至2016年12月的结肠镜检查数据,计算各个预警症状的诊断敏感度、特异度、阳性预测值、阴性预测值、阳性似然比和阴性似然比。结果:预警症状总的诊断敏感度和特异度分别是6.63%和94.33%。所有的预警症状诊断敏感度最高的是便血,敏感度为19.28%,最低的是腹泻,敏感度为2.41%。相对而言,便血和长期腹痛的准确度较高,分别达到了19.28%和11.45%。除了长期腹痛之外,其他所有的预警症状的诊断特异度都达到了90%以上。结论:超过一半的结直肠癌患者没有出现预警症状,用预警症状来诊断结直肠癌具有较低的敏感度和较高的特异度,需要更多的研究来证明预警症状的临床意义。     

Hypoxic colorectal cancer-secreted exosomes deliver miR-210-3p to normoxic tumor cells to elicit a protumoral effect

Hypoxia, the most common feature in the tumor microenvironment, is closely related to tumor malignant progression and poor patient’s prognosis. Exosomes, initially recognized as cellular “garbage dumpsters”, are now known to be important mediums for mediating cellular communication in tumor microenvironment. However, the mechanisms of hypoxic tumor cell-derived exosomes facilitate colorectal cancer progression still need further exploration. In the present study, we found that exosomes from hypoxic colorectal cancer cells (H-Exos) promoted G1-S cycle transition and proliferation while preventing the apoptosis of colorectal cancer cells by transmitting miR-210-3p to normoxic tumor cells. Mechanistic investigation indicated that miR-210-3p from H-Exos elicited its protumoral effect via suppressing CELF2 expression. A preclinical study further confirmed that H-Exos could promote tumorigenesis in vivo. Clinically, the expression of miR-210-3p in circulating plasma exosomes was markedly upregulated in colorectal cancer patients, which were closely associated with multiple unfavorable clinicopathological features. Taken together, these results suggest that hypoxia may stimulate colorectal cancer cells to secrete miR-210-3p-enriched exosomes in tumor microenvironment, which elicit protumoral effects by inhibiting CELF2 expression. These findings provide new insights on the mechanism of colorectal cancer progression and potential therapeutic targets for colorectal cancer.     

Overexpression of choline kinase is a frequent feature in human tumor-derived cell lines and in lung,prostate, and colorectal human cancers

Carcinogenesis is a long process that results in the accumulation of genetic alterations primarily in genes involved in the regulation of signalling pathways relevant for the regulation of cell growth and the cell cycle. Alteration of additional genes regulating cell adhesion and migration, angiogenesis, apoptosis, and drug resistance confers to the cancer cells a more malignant phenotype. Genes that participate in the regulation of some critical metabolic pathways are also altered during this process. Choline kinase (ChoK) has been reported to belong to the latter family of cancer-related genes. Recently, we have reported that increased activity of ChoK is observed in human breast carcinomas. Here, we provide further evidence that ChoK dysregulation is a frequent event found in a variety of human tumors such as lung, colorectal, and prostate tumors. Furthermore, a large panel of human tumor-derived cell lines also show increased ChoK activity when compared to appropriate non-tumorigenic or primary cells. These findings strongly support the role of ChoK alterations in the carcinogenic process in human tumors, suggesting that ChoK could be used as a tumor marker.     

Cell cycle-related signaling pathways modulated by peripheral benzodiazepine receptor ligands in colorectal cancer cells

Specific ligands of the peripheral benzodiazepine receptor (PBR) have been shown to induce both apoptosis and G1/G0 cell cycle arrest in colorectal cancers. The signaling pathways leading to cell cycle arrest are still unknown. Using cDNA array technology, we identified signaling molecules involved in cell cycle arrest induced by the PBR ligands FGIN-1-27 and PK 11195. Differential gene expression was confirmed by semi-quantitative RT-PCR or Western blot analysis of gene products. The PBR ligand-mediated signaling involved the upregulation of the cyclin-dependent kinase inhibitors p21WAF1/CIP1 and p27Kip1, cdc16, and the cell cycle inhibitors gadd45 and gadd153, the downregulation of the cyclins D1 and B1, as well as the inactivation of ERK1/2. The p21-deficient colorectal cancer cell line HCT116 p21-/- was significantly less sensitive to PBR ligands than the parental HCT116 wild-type cells, demonstrating the functional involvement of p21WAF1/CIP1 in PBR ligand-mediated G1 arrest. This study thus revealed PBR ligand-triggered signaling pathways leading to cell cycle arrest. Moreover, we showed the functional implication and interaction of differentially expressed gene products and provided a model of signaling pathways involved in PBR ligand-induced G1 arrest. These results form the basis for future PBR ligand-mediated therapeutic approaches.