Significance of longitudinal Epstein-Barr virus DNA combined with multipoint tumor response for dynamic risk stratification and treatment adaptation in nasopharyngeal carcinoma.

Dynamic therapy response is strongly associated with cancer outcomes. This study aimed to evaluate the significance of longitudinal Epstein-Barr virus (EBV) DNA and radiological tumor regression in risk stratification and response-adaptive treatment in locally-advanced nasopharyngeal carcinoma (LA-NPC). In total, 1,312 patients from two centers were assigned to the training and validation cohorts. Based on the multipoint examination of EBV-DNA and tumor response, four post-induction chemotherapy, four mid-radiotherapy, and four post-radiotherapy subgroups were established. Then seven phenotypes were further generated according to different permutations and combinations. These phenotypes were subsequently congregated into four response clusters, which reflect distinct biological treatment responses. The four response clusters correlated with an evident 5-year progression-free survival in both the training and external validation cohorts (5-year: training cohort 91.1%, 82.8%, 30.6%, and 10.0%; external validation 94.4%, 55.6%, 40.0%, and 12.7%) had superior prognostic performance compared to TNM staging and nomogram model (concordance index: training cohort-0.825 vs. 0.603 vs. 0.756 and external validation-0.834 vs. 0.606 vs. 0.789). Importantly, the response clusters exhibited an excellent capability in selecting candidates who can benefit from adjuvant chemotherapy. In conclusion, risk stratification based on the dynamic assessment of both radiological and biological responses can significantly enhance prognostic insights and shed light on individualized treatment modifications in LA-NPCs.

Distinctive targetable genotypes of younger patients with lung adenocarcinoma: a cBioPortal for cancer genomics data base analysis.

There is still limited comprehensive genotyping data about young patients with lung adenocarcinoma. Herein, next generation sequencing (NGS) data of lung adenocarcinoma patients was retrospectively analyzed to evaluate the relationship between young age at diagnosis and the comprehensive molecular characteristics. The cBioPortal for Cancer Genomics database was queried for cancer genomic studies of lung adenocarcinoma and a cohort of 773 patients with complete cancer genomics data was selected from 2 of 11 studies. The relationship between age at diagnosis and frequency of targetable genotypes was analyzed and verified in another cohort composed of 177 Chinese lung adenocarcinoma patients undergoing NGS assay. Of the 773 eligible lung adenocarcinoma patients, younger age was associated with an increased likelihood of a targetable genotype (P < .001). Specifically, a higher prevalence of EGFR mutations (P = .005), ALK arrangements, ROS1 arrangements (P = .035) and RET arrangements (P < .001) were identified in younger patients. The frequency of KRAS mutations (P < .001) was significantly associated with older age at diagnosis and a similar trend existed for MET (P = .057) but not BRAF-V600E (P = .686) and ERBB2 (P = .083). Additionally, an age at diagnosis of 45 years was found to be a feasible cutoff point to differentiate the younger from the older patients by comprehensive molecular characteristics. These results indicated that younger patients with lung adenocarcinoma were associated with an increased likelihood of harboring a targetable genotype. Distinctive molecular characteristics were identified in patients younger than 45 years with lung adenocarcinoma, which highlights the importance of the NGS assay and personalized therapy in this subpopulation.

Effect of interventional embolotherapy on FHIT and p16 expression in hepatocellular carcinoma patients.

Effects of interventional embolotherapy on the expression of fragile histidine triad (FHIT) and p16 in hepatocellular carcinoma (HCC) patients were investigated. Patients with primary HCC who were definitely diagnosed and treated in the Department of Gastroenterology in Qingdao Central Hospital from March 2014 to March 2016 were selected, and they underwent interventional embolotherapy. HCC and cancer-adjacent tissues of the patients were harvested for immunohistochemical staining. The correlation between the expression levels of FHIT and p16 was analyzed at the gene and protein level. Clinical data were collected, and whether they were correlated with the expression of FHIT and p16 was investigated. The expression levels of FHIT and p16 in primary HCC tissues were remarkably lower than that in cancer-adjacent tissues (P<0.05). In HCC tissues, FHIT expression was obviously positively correlated with p16 expression (Spearman's correlation coefficient, r=0.308; P=0.025). FHIT was related to HCC tumor-node-metastasis (TNM) staging, the differentiation degree in Edmondson-Steiner grading, lymph node metastasis and portal vein thrombosis (P<0.05 in all comparisons), whereas, p16 was associated with tumor size and the differentiation degree in Edmondson-Steiner grading (P<0.05 in all comparisons). The expression of FHIT and p16 genes and proteins in HCC tissues were obviously lower than those in cancer-adjacent tissues (P<0.05 in all comparisons). FHIT and p16 genes, as tumor suppressor genes, inhibit the proliferation of HCC, and there is a positive correlation between them. The proteins of the FHIT and p16 can be used as new indicators for clinical detection, thus providing a new method for clinical diagnosis.

Helicobacter pylori promotes invasion and metastasis of gastric cancer cells through activation of AP-1 and up-regulation of CACUL1.

Infection with Helicobacter pylori is important in the development and progression of gastric cancer. However, the mechanisms that regulate this activation in gastric tumors remain elusive. CACUL1 has been cloned and identified as a novel gene that is expressed in many types of cancer and is involved in cell cycle regulation and tumor growth. The current study aimed to examine the expression of CACUL1 in gastric cancer samples and analyze its correlation with H. pylori infection. We found that CACUL1 was highly expressed in gastric cancer tissues and negatively correlated with gastric cancer differentiation and TNM stage. In addition, CACUL1 expression was high in H. pylori-infected tissues compared with H. pylori non-infected tissue. We found that H. pylori could up-regulate CACUL1 expression through activating protein 1. The up-regulation of CACUL1 expression could promote matrix metalloproteinase 9 and Slug expression to increase invasion and metastasis of tumor cells. These results suggested that H. pylori-triggered CACUL1 production occurred in an activating protein 1-dependent manner and regulated matrix metalloproteinase 9 and Slug expression to affect the invasion and metastasis of tumor cells. Therefore, CACUL1 is a potential therapeutic target for the treatment of aggressive gastric cancer.

[Effect of cell cycle-related novel gene CACUL1 on the apoptosis of colorectal cancer cells in vitro].

OBJECTIVE: To investigate the role of the cell cycle-related novel gene CDK2-associated, culin clomain 1(CACUL1) in tumor cell apopotosis and explore the relationship between CACUL1 and apoptosis regulation. METHODS: We induced the cell cycle arrest by ultraviolet radiation and chemotherapeutic drugs and then studied the expression of CACUL1 in cell DNA damage state. Meanwhile, Western blotting, Northern blotting and other methods were applied to detect the expression of the CACUL1 at both protein and mRNA levels and analyze their relationships with p53 in p53 wild-type and knock-out colorectal cancer cells. RESULTS: The CACUL1 was proved related to the regulation of apoptosis. In the case of DNA damage induced by ultraviolet radiation and chemotherapeutic drugs, the expression of CACUL1 protein peaked at 2 h, and with time went by, the expression of CACUL1 gradually decreased. The increase of CACUL1 expression was independent of p53. Northern blotting revealed that the increased expression of CACUL1 was post-transcriptional regulation. It was also found that the high expression of CACUL1 inhibited cell apoptosis induced by ultraviolet radiation and chemotherapeutic drugs. CONCLUSION: The role of CACUL1 in cell apoptosis is to help cells cross the G1/S checkpoints in a posttranscriptional regulation of p53-independent manner, thus facilitating cell survival.

The deoxycholic acid targets miRNA-dependent CAC1 gene expression in multidrug resistance of human colorectal cancer.

There is evidence indicating that bile acid is a promoter of colorectal cancer. Deoxycholic acid modifies apoptosis and proliferation by affecting intracellular signaling and gene expression. We are interested in revealing the relationship between deregulated miRNAs and deoxycholic acid in colorectal cancer development. We found that miR-199a-5p was expressed at a low level in human primary colonic epithelial cells treated with deoxycholic acid compared with control, and miR-199a-5p was significantly down-regulated in colorectal cancer tissues. The miR-199a-5p expression in colorectal cancer cells led to the suppression of tumor cell growth, migration and invasion. We further identified CAC1, a cell cycle-related protein expressed in colorectal cancer, as a miR-199a-5p target. We demonstrated that CAC1 is over-expressed in malignant tumors, and cellular CAC1 depletion resulted in cancer growth suppression. HCT-8 cells transfected with a miR-199a-5p mimic or inhibitor had a decrease or increase in CAC1 protein levels, respectively. The results of the luciferase reporter gene analysis demonstrated that CAC1 was a direct miR-199a-5p target. The high miR-199a-5p expression and low CAC1 protein expression reverse the tumor cell drug resistance. We conclude that miR-199a-5p can regulate CAC1 and function as a tumor suppressor in colorectal cancer. Therefore, the potential roles of deoxycholic acid in carcinogenesis are to decrease miR-199a-5p expression and/or increase the expression of CAC1, which contributes to tumorigenesis in patients with CRC. These findings suggest that miR-199a-5p is a useful therapeutic target for colorectal cancer.

Pleiotrophin is a potential colorectal cancer prognostic factor that promotes VEGF expression and induces angiogenesis in colorectal cancer.

PURPOSE: Pleiotrophin (PTN) is an important developmental secretory cytokine expressed in many types of cancer and involved in angiogenesis and tumor growth; however, the significance of PTN expression in colorectal cancer (CRC) has not been established. METHODS: Immunohistochemistry, western blot, and enzyme-linked immunosorbent assay were used to detect PTN expression in CRC patients. The relationship between PTN expression and clinicopathological characteristics and survival time was statistically analyzed, and the relationship between PTN and vascular endothelial growth factor (VEGF) in tumor angiogenesis was further analyzed. RESULTS: Of CRC tissues, 74.70% (62/83) stained positive, with a strong positive ratio of 60.24% (50/83). The expression of PTN in CRC tissues was much higher than in normal colorectal tissues. PTN serum levels in CRC patients (mean = 254.59 ± 261.76 pg/ml) were significantly higher than those of normal volunteers (mean = 115.23 ± 79.53 pg/ml; p < 0.001). PTN expression was related to CRC differentiation and TNM staging. High level of PTN is a predictor of a poor prognosis and high expression of PTN is accompanied by high expression of VEGF in CRC patients. Investigation of the relationship between PTN and VEGF revealed that PTN, through the PTN/RPTPß/ζ signaling pathway, increased tyrosine phosphorylation of ß-catenin, leading to an increase in VEGF. CONCLUSIONS: Our study identifies PTN as an essential growth factor for CRC. PTN promotes VEGF expression and cooperates with VEGF in promoting CRC angiogenesis. PTN could serve as a prognostic factor for this cancer. Considering that PTN shows very limited expression in normal tissue, it may represent an attractive new target for CRC therapy.