Supplemental Methods from Discovery and Validation of Circulating Biomarkers of Colorectal Adenoma by High-Depth Small RNA Sequencing
Brian S. RobertsAndrew A. HardiganDianna E. MooreRyne C. RamakerAngela L. JonesMeredith B. Fitz-GeraldGregory M. CooperC. Mel WilcoxRobert P. KimberlyR Myers
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<p>Detailed methods including analysis</p>Keywords:
Colorectal adenoma
This study aimed to investigate the clinical significance of changes in vitamin D [25(OH)D] levels and vitamin D receptor (VDR) mRNA expression in colorectal adenoma development.Plasma concentrations of 25(OH)D and mRNA expression of VDR in tissues were determined by enzyme-linked immunosorbent assay (ELISA) and real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), respectively. In addition, the concentration of plasma 25(OH)D and levels of VDR mRNA in tissues were compared among healthy individuals and adenoma and adenocarcinoma patients.Vitamin D receptor expression in colorectal adenocarcinoma tissues was significantly lower than that in para-cancerous tissues that were >5 cm away from malignant tumor sites (p < 0.01). The level of VDR expression in normal colorectal tissues from healthy individuals was significantly higher than that in colorectal adenomas (p < 0.01) and colorectal adenocarcinomas (p < 0.01); however, the VDR expression was not significantly different between colorectal adenomas and colorectal adenocarcinomas (p = 0.106). The concentration of 25(OH)D in healthy individuals was significantly higher than that in patients with colorectal adenomas (p < 0.01) and colorectal adenocarcinomas (p < 0.01); however, the concentration of 25(OH)D was not significantly different between colorectal adenomas and colorectal adenocarcinomas (p = 0.489). A low concentration of 25(OH)D was considered a risk factor for colorectal adenoma and colorectal adenocarcinoma, with odds ratios of 4.875 and 2.925, respectively.The 25(OH)D levels and VDR mRNA expression might be associated with the development of colorectal adenoma and its progression to adenocarcinoma.
Colorectal adenoma
Colorectal adenocarcinoma
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Objective To investigate the expression and significance of δ-catenin in colorectal cancer(CRC),and explore the correlation between8-catenin expression and cell proliferation in colorectal cancer.Methods The expressions of 8-catenin and Ki-67 in 120 specimens of colorectal cancer were detected by immunohistochemistry in tissue microassay.The expression of 8-catenin was also determined in 30 paired colorectal cancer and normal colorectum by Western blot.Results Overexpression of 8-catenin was detected in 65.83%(79/120) of the 120 human colorectal cancer tissues,which was significantly higher than that in normal colorectum.The positive expression of 8-catenin was higher in advanced TNM stages(Ⅲ+ Ⅳ)of colorectal cancer(78.05%,32/41),compared to lower stages(Ⅰ+Ⅱ)(59.49%,47/79)(x~2=4.132,P= 0.042).The positive expression of 8-catenin was higher in poor differentiated colorectal cancer(82.14%,23/28),compared to well/moderate differentiated colorectal cancer(60.87%,56/92)(x~2=4-319,P = 0.038).The positive expression of 8-catenin was higher in colorectal cancer with lymph node metastasis(77.05%,47/61),compared to colorectal cancer without lymph node metastasis(54.24%,32/59)(x~2=6-939,P = 0.008).In addition,we also found that the overexpression of 8-catenin was positively correlated with proliferation of colorectal cancer which marked by Ki-67 staining in colorectal cancer(r=0.334,P 0.01).Conclusion 8-catenin overexpression might be involved in the initiation and progression of colorectal cancer.
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Objective To detect the expression and role of PTTG mRNA in human colorectal cancer.Methods The expression of PTTG mRNA was evaluated in 12 normal colorectal tissues,20 colorectal adenoma tissues and 44 colorectal cancer tissues by RT-PCR.Results The expression of PTTG mRNA in colorectal cancer was significantly higher than that in colorectal adenoma and normal colorectal tissues.The PTTG mRNA expression in the Dukes C,D colorectal cancer was higher than that in the Dukes A,B cancer(P0.05).The expression in the colorectal cancer with lymph node metastasis was higher than that in the cancer without lymph node metastasis(P0.05).Conclusion The expression of PTTG mRNA increases in colorectal cancer,and is related with cell differentiation and metastasis.The abnormal expression of PTTG probably participates in genesis and development of colorectal cancers.
Colorectal adenoma
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Objective To explore the relationship among HER-2 gene, K-RAS gene, the carcinogenesis mechanism of colorectal cancer and the prognosis by the determination of the expression of HER-2 and K-RAS in colorectal cancer tissues. Methods The expression of HER-2 and K-RAS was detected with immunohistochemical methods in normal mucosal tissue, colorectal adenoma, colorectal cancer and metastatic lymph nodes. Results The positive rates of HER-2 and K RAS high expression were 67.5% and 51.2% respectively, in colorectal cancer, and 80.0% and 33.3% respectively in colorectal adenoma, while those in normal mucosal tissue were only 33.3% and 0.The expression of HER-2 and K-RAS in colorectal cancer and colorectal adenoma were significantly higher than those in normal mucosal tissue, but no significant differences existed between colorectal cancer and colorectal adenoma. In colorectal cancer, high expression of both proteins occurred in 36.3% of the cases. The positive rate of HER-2 hyperexpression in cell membrane was 38.2%, which showed a positive correlation with depth of invasion, high expression of K-RAS was not correlated with clinicopathologic parameters. In the metastatic lymph nodes, the HER-2 hyperexpression was positively correlated with K-RAS hyperexpression (r=0.458, P＜0.05). There was no significant association between their high expressions and prognosis in colorectal carcinoma. Conclusion HER-2 and K-RAS may play a combined role in the development of colorectal cancer. Hyperexpression of HER-2 in cell membrane was significantly associated with invasiveness. There was no significant association between their high expressions and prognosis in colorectal carcinoma.
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Objective To study the expression of COX-2 in the early colorectal cancers(ECCs) and its clinic significance. Methods COX-2 expression was examined by immunohistochemical staining in thirty-two early colorectal cancer specimens surgically resected, thirty-three colorectal adenoma and eighteen normal colorectal mucosal tissues taken by endoscopy biopsy.Results COX-2 expression, divided into 4 grades from ”-”to“”, is respectively 83.3%、16.7%、0%、0% in normal colonic mucosal tissues; 12.1%、42.4%、36.4%、9.1% in colorectal adenoma; 6.3%、28.1%、46.9%、18.7% in ECCs. The differences in the COX-2 expression between ECCs and normal colorectal mucosae as well as between colorectal adenoma and normal colorectal mucosae were statistically significant (P0.01).But there was no significant difference between ECCs and colorectal adenoma. There is no relationship between expression of COX-2 and clinicopathological features of either ECCs or colorectal adenoma.COX-1 is only constitutively expressed at low levels in the ECCs, colorectal adenoma and normal colorectal mucosae. Conclusion COX-2 expression is gradually up-regulated in the development course of normal epithelium to colorectal adenoma and early colorectal cancer.COX-2 expression is a early incidents in the pathogenesis of colorectal cancer, and it can not be considered as a marker to diagnose ECC.
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Abstract Colorectal cancer is a crucial health-threatening problem. In recent years, the treatment of colorectal cancer has continued improved and update. But the prognosis of advanced colorectal cancer is still disappointing. Galecitn-9 is a member of the galectin family which has been verified to have multiple biological regulatory functions. Our team has been studying the clinical application of the galectin family in gastric and colorectal cancer. However, we do not yet unveil the correlation between Galecitn-9 and colorectal cancer. This study aimed to elucidate the expression of Galecitn-9 in colorectal cancer and the effect of Galecitn-9 on colorectal cancer proliferation, migration and invasion.
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Objective To study the expression of KLF6 protein in colorectal cancer(CRC) and its correlation with serum CEA level. Methods The expression of KLF6 protein in colorectal cancer,colorectal adenoma,and normal colorectal tissues was detected by immunohistochemistry.Serum CEA level in patients with colorectal cancer was measured by ELISA. Results The expression of KLF6 protein in normal colorectal tissues,colorectal adenoma and colorectal cancer were 85.7%,76.5% and 43.6%,respectively,with significant differences among them(X2=25.20,P0.01).KLF6 expression was significantly correlated with differentiation grade,lymph node metastasis and TNM stage(P0.05).However,no significant correlation between KLF6 expression and CEA was found(P0.05). Conclusion Reducd expression of KLF6 in CRC suggests its inhibition on the oncogenesis of colorectal cancer.KLF6 is a useful marker for cancer risk evaluation of colorectal cancer.
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Background: Several studies have investigated the possible role of John Cunningham virus (JCV) in colorectal carcinogenesis, however the results were conflicting. The aim of this meta-analysis was to examine the association between JCV and colorectal tumors with special reference to early-onset colorectal cancer (EO-CRC).Methods: A systematic search was conducted through the Embase, Cochrane Collaboration, and PubMed databases for studies comparing the presence of JCV DNA in colorectal cancerous and non-cancerous tissues. Countries where the studies were conducted were categorized into high and low prevalence settings for EO-CRC, and according to the incidence rates of EO-CRC into rising-trend, stable-trend, and decreasing-trend settings. The strength of association was estimated by Peto odds ratio and 95% confidence interval.Results: The meta-analysis showed that JCV increased the odds for colorectal cancer by 4.1-fold, and for colorectal adenoma by 6-fold in comparison to controls. Compared with adjacent and non-adjacent colorectal tissues, JCV increased the odds for colorectal cancer by 4-fold and 4.2-fold, and for colorectal adenoma by 6.6-fold and 5.6-fold, respectively. The odds for colorectal tumor development with JCV infection were significantly higher in the high-prevalence settings than in the low-prevalence settings when compared with controls (P = 0.01) and matched adjacent colorectal tissues (P = 0.0002). Similarly, the odds for colorectal tumor development trended to be higher in the rising-trend settings than in the stable-trend settings when compared with controls (P = 0.05); no JCV DNA was detected in the decreasing-trend settings in both cancerous and non-cancerous colorectal tissues. Conclusion: JCV infection is associated with increased risk of both colorectal cancer and adenoma, and is likely involved in early stage of carcinogenesis. The higher odds for colorectal tumor development in the high-prevalence and rising-trend settings for EO-CRC indicate that JCV may play a role in the international variations and temporal trends of EO-CRC in several parts of the world.
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