Systemic adiponectin levels in colorectal cancer and adenoma: a systematic review and meta-analysis.

BACKGROUND: Obesity is a well-established risk factor in the development of colorectal cancer; however, the mechanism mediating this relationship is not well understood. The adipokine, adiponectin, has an inverse relationship with obesity. Experimental studies have shown adiponectin to have dichotomous inflammatory and tumorigenic roles. Its role in the development of colorectal cancer, including the potential effect of its increase following bariatric surgery, is not yet clear. There are conflicting results from studies evaluating this relationship. This study sought to provide a systematic review and meta-analysis to examine the association between systemic adiponectin levels in patients with colorectal cancer and adenoma. METHODS: An electronic literature search was performed using PubMed, EMBASE, Web of Science as well as gray literature. Articles were screened for inclusion criteria and assessed for quality using the Newcastle-Ottawa Scale. Pooled mean differences were calculated using a random effects model. Subgroup and meta-regression analyses were performed to identify potential sources of heterogeneity. RESULTS: Thirty-two observational studies comparing systemic adiponectin in colorectal cancer vs healthy controls were included. Colorectal cancer cases had lower systemic adiponectin levels (overall pooled mean difference = -1.05 µg/ml [95% CI: -1.99; -0.12] p = 0.03); however, significant heterogeneity was present (I2 = 95% p < 0.01). Subgroup and meta- regression analyses results could not identify a source of the significant heterogeneity across the studies. CONCLUSIONS: Studies suggest a trend towards lower systemic adiponectin levels in colorectal cancer patients, but the heterogeneity observed showed current evidence is not sufficient to definitively draw any conclusions. These data, however, suggest rising adiponectin is unlikely to account for the reported observation of increased CRC following bariatric surgery. Further studies with prospective age, race, and BMI-matched cohorts, and standardized adiponectin measurements may provide a better understanding of this relationship.

The role of the miR-200 family in epithelial-mesenchymal transition in colorectal cancer: a systematic review.

Colorectal cancer (CRC) is associated with significant morbidity and mortality as many patients are diagnosed with advanced stage disease. MicroRNAs are small, noncoding RNA molecules that have a major role in gene expression regulation and are dysregulated in CRC. The miR-200 family is involved in epithelial-mesenchymal transition (EMT). This systematic review describes the roles of the miR-200 family in EMT in CRC. A search of electronic databases (PubMed and Embase) was conducted between January 2000 and July 2017. Both in vitro and human studies reporting on the miR-200 family and CRC were included. Studies describing molecular pathways and the role of the miR-200 family in the diagnostic and therapeutic management of CRC were analyzed. Thirty-four studies (22 in vitro and 18 human studies) were included. miR-200 family expression is regulated epigenetically and via transcriptional factor regulation. In vitro studies show that transfection of miR-200 family members into chemo-resistant colon cancer cell lines results in improved chemo-sensitivity and epithelial phenotype restoration. There is intra-tumoral variability in the tissue expression of miR-200 family members with decreased expression at the invasive front. Clinical studies in CRC patients have shown decreased primary tumor tissue expression of miR-429, miR-200a and miR-200c may be associated with worse survival. Conversely, increased blood levels of miR-141, miR-200a and miR-200c may be associated with worse outcomes. The miR-200 family has a central role in EMT. The miR200 family has potential for both prognostic and therapeutic management of CRC.

Blood-based microRNAs as biomarkers for the diagnosis of colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: Colorectal cancer (CRC) is common and associated with significant mortality. Current screening methods for CRC lack patient compliance. microRNAs (miRNAs), identified in body fluids, are negative regulators of gene expression and are dysregulated in many cancers, including CRC. This paper summarises studies identifying blood-based miRNAs dysregulated in CRC compared with healthy controls in an attempt to evaluate their use as a screening tool for the diagnosis of CRC. METHODS: A search of electronic databases (PubMed and EMBASE) and grey literature was performed between January 2002 and April 2016. Studies reporting plasma or serum miRNAs in the diagnosis of CRC compared with healthy controls were selected. Patient demographics, type of patient sample (serum or plasma), method of miRNA detection, type of normalisation, and the number of significantly dysregulated miRNAs identified were recorded. Statistical evaluation of dysregulated miRNAs using sensitivity, specificity, and area under the curve (AUC) was performed. RESULTS: Thirty-four studies investigating plasma or serum miRNAs in the diagnosis of CRC were included. A total of 31 miRNAs were found to be either upregulated (n=17) or downregulated (n=14) in CRC cases as compared with controls. Fourteen studies identified panels of ⩾2 dysregulated miRNAs. The highest AUC, 0.943, was identified using a panel of 4 miRNAs with 83.3% sensitivity and 93.1% specificity. Meta-analysis of studies identifying a single dysregulated miRNA in CRC cases compared with controls was performed. Overall sensitivity and specificity of 28 individual miRNAs in the diagnosis of CRC were 76% (95% CI 72%-80%) and 76% (95% CI 72%-80%), respectively, indicating good discriminative ability of miRNAs as biomarkers for CRC. These data did not change with sensitivity analyses. CONCLUSIONS: Blood-based miRNAs distinguish patients with CRC from healthy controls with high sensitivity and specificity comparable to other common and invasive currently used screening methods for CRC. In future, miRNAs may be used as a relatively non-invasive blood-based marker for detection of CRC.

A Highly Predictive Model for Diagnosis of Colorectal Neoplasms Using Plasma MicroRNA: Improving Specificity and Sensitivity.

OBJECTIVE: To develop a plasma-based microRNA (miRNA) diagnostic assay specific for colorectal neoplasms, building upon our prior work. BACKGROUND: Colorectal neoplasms [colorectal cancer (CRC) and colorectal advanced adenoma (CAA)] frequently develop in individuals at ages when other common cancers also occur. Current screening methods lack sensitivity, specificity, and have poor patient compliance. METHODS: Plasma was screened for 380 miRNAs using microfluidic array technology from a "Training" cohort of 60 patients, (10 each) control, CRC, CAA, breast cancer, pancreatic cancer, and lung cancer. We identified uniquely dysregulated miRNAs specific for colorectal neoplasia (P < 0.05, false discovery rate: 5%, adjusted α = 0.0038). These miRNAs were evaluated using single assays in a "Test" cohort of 120 patients. A mathematical model was developed to predict blinded sample identity in a 150 patient "Validation" cohort using repeat-sub-sampling validation of the testing dataset with 1000 iterations each to assess model detection accuracy. RESULTS: Seven miRNAs (miR-21, miR-29c, miR-122, miR-192, miR-346, miR-372, and miR-374a) were selected based upon P value, area under the curve (AUC), fold change, and biological plausibility. Area under the curve (±95% confidence interval) for "Test" cohort comparisons were 0.91 (0.85-0.96) between all neoplasia and controls, 0.79 (0.70-0.88) between colorectal neoplasia and other cancers, and 0.98 (0.96-1.0) between CRC and colorectal adenomas. In our "Validation" cohort, our mathematical model predicted blinded sample identity with 69% to 77% accuracy, 67% to 76% accuracy, and 86% to 90% accuracy for each comparison, respectively. CONCLUSIONS: Our plasma miRNA assay and prediction model differentiate colorectal neoplasia from patients with other neoplasms and from controls with higher sensitivity and specificity compared with current clinical standards.

Sex differences and plasticity in dehydration tolerance: insight from a tropical liverwort.

BACKGROUND AND AIMS: Adaptations allowing plants to cope with drying are particularly relevant in the light of predicted climate change. Dehydration tolerance (DhT, also dehydration-tolerant) is one such adaptation enabling tissue to survive substantial drying. A great deal of work has been conducted on highly DhT species. However, bryophytes showing less intense and variable DhT are understudied, despite the potential for these species to provide an informative link between highly tolerant and sensitive species. In this study, we tested the degree to which DhT varies across populations and the sexes of a species expected to exhibit a moderate DhT phenotype. METHODS: To test predicted patterns of tolerance we assessed DhT in males and females of Marchantia inflexa from two distinct habitat types that differ in water availability. Both common garden and field-collected tissue was subjected to drying assays at multiple intensities and recovery was monitored by chlorophyll florescence. Verification studies were conducted to confirm the level of dehydration, the rate of drying and the associated changes in photosynthetic physiology. KEY RESULTS: We confirmed our expectation that M. inflexa is able to tolerate moderate dehydration. We also found that females exhibited higher DhT than males, but populations did not differ in DhT when cultured in a common garden. However, field-collected samples exhibited differences in DhT corresponding to environmental dryness, suggesting plasticity in DhT. CONCLUSIONS: By studying a less extreme DhT phenotype we gained insight into how more sensitive (yet still tolerant) organisms cope with dehydration. Additionally, the identified sex-specific variation in DhT may explain ecological patterns such as female-biased sex ratios. Furthermore, plasticity in DhT has the potential to inform management practices aimed at increasing tolerance to drought conditions.

The microRNA-200 family acts as an oncogene in colorectal cancer by inhibiting the tumor suppressor RASSF2.

This study aimed to determine whether manipulation of the microRNA-200 (miR-200) family could influence colon adenocarcinoma cell behavior. The miR-200 family has a significant role in tumor suppression and functions as an oncogene. In vitro studies on gain and loss of function with small interfering RNA demonstrated that the miR-200 family could regulate RASSF2 expression. Knockdown of the miR-200 family in the HT-29 colon cancer cell line increased KRAS expression but decreased signaling in the MAPK/ERK signaling pathway through reduced ERK phosphorylation. Increased expression of the miR-200 family in the CCD-841 colon epithelium cell line increased KRAS expression and led to increased signaling in the MAPK/ERK signaling pathway but increased ERK phosphorylation. Functionally, knockdown of the miR-200 family led to decreased cell proliferation in the HT-29 cells; therefore, increased miR-200 family expression could increase cell proliferation in the CCD-841 cell line. The present study included a large paired miR array dataset (n=632), in which the miR-200 family was significantly found to be increased in colon cancer when compared with normal adjacent colon epithelium. In a miR-seq dataset (n=199), the study found that miR-200 family expression was increased in localized colon cancer compared with metastatic disease. Decreased expression was associated with poorer overall survival. The miR-200 family directly targeted RASSF2 and was inversely correlated with RASSF2 expression (n=199, all P<0.001). Despite the well-defined role of the miR-200 family in tumor suppression, the present findings demonstrated a novel function of the miR-200 family in tumor proliferation.