Identification and Validation of MicroRNA Profiles in Fecal Samples for Detection of Colorectal Cancer

Durán-Sanchón, Saray; Moreno, Lorena; Augé, Josep M.; Serra-Burriel, Miquel; Cuatrecasas, Míriam; Moreira, Letícia; Martin, Agatha; Serradesanferm, Anna; Pozo, Àngels; Costa, Rosa; Lacy, Antonio de; Pellisé, María; Lozano, Juan José; Gironella, Meritxell; Castells, Antoni

doi:10.1053/j.gastro.2019.10.005

Cited by 57 publications

(74 citation statements)

References 40 publications

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“…[25][26][27] Recently, miR-421 was shown to be upregulated in fecal samples from patients with advanced CRC neoplasms. 28 In the present study, we found that the expression of miR-421 was increased in CRC tissues compared with adjacent noncancerous tissues.…”

Section: Discussionsupporting

confidence: 53%

MicroRNA-421 Inhibits Apoptosis by Downregulating Caspase-3 in Human Colorectal Cancer

Zhou

Cheng

Wan

et al. 2020

CMAR

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Dysregulated microRNAs (miRNAs/miRs) have been reported to play significant roles in pathogenesis of colorectal cancer (CRC). Previous studies have demonstrated that miR-421 regulates apoptosis in some cancers. Caspase-3 plays a key role in apoptosis, but the relationship between miR-421 and caspase-3 in CRC has not been determined. In this study, we investigated the role of miR-421 in CRC and the relationship between miR-421 and caspase-3. Methods: Expression of miR-421 and caspase-3 were detected in human paired CRC cancer tissues and corresponding paracancerous tissues. In situ detection of tissue, apoptosis was performed via the TUNEL assay. HCT116 and SW480 cell lines were subjected to several in vitro experiments to explore the relationship between miRNA421 and caspase-3 during apoptosis using miR421 mimics/antagomir and luciferase reporter assay. Apoptosis was measured by determining the levels and activity of caspase-3 as well as DNA fragmentation. Luciferase reporter assay was performed to determine the potential interaction of miR-421 with caspase-3. Results: The results showed that the expression of miR-421 in cancer tissues was higher than that in corresponding paracancerous tissues. Inhibition of miR-421 induced apoptosis, as shown by the upregulation of caspase-3 activity and expression as well as DNA fragmentation, which were attenuated by miR-421 mimic. We further showed that miR-421 targeted and inhibited CASP3 expression by targeting sites located in the 3ʹ-untranslated region (3ʹ-UTR) of CASP3 mRNA. Conclusion: This study demonstrated an anti-apoptotic role of miR-421 in CRC and identified caspase-3 gene as a direct target of miR-421. These findings provide a potential treatment strategy using miR-421 as a therapeutic target for CRC.

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Section: Discussionsupporting

confidence: 53%

MicroRNA-421 Inhibits Apoptosis by Downregulating Caspase-3 in Human Colorectal Cancer

Zhou

Cheng

Wan

et al. 2020

CMAR

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“…Due to their biochemical stability in the fecal medium [25, 26], these miRNAs should theoretically be good candidates for noninvasive diagnosis of inflammatory GI conditions. Recently, this concept has been validated successfully in screening programs for colorectal cancer [27] and IBD [19].…”

Section: Discussionmentioning

confidence: 99%

A Prospective Cohort Study of Fecal miR-223 and miR-451a as Noninvasive and Specific Biomarkers for Diagnosis of Necrotizing Enterocolitis in Preterm Infants

Chan

Lam

et al. 2020

Neonatology

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Objective: The objective of this study is to evaluate the usefulness of fecal microRNA (miR)-223 and miR-451a, as novel noninvasive biomarkers for early diagnosis of necrotizing enterocolitis (NEC) in preterm infants. Methods: Among the top-listed target miRNAs in our previous differential microarray analysis, miR-223 and miR-451a were quantified in a pilot validation case-controlled study (NEC vs. non-NEC/nonsepsis infants; n = 6 in each group). A definitive prospective cohort study (n = 218) further assessed their clinical usefulness as noninvasive and specific diagnostic biomarkers. Fecal calprotectin was quantified in parallel for comparison. Results: Of 43 proven NEC cases in the cohort study, 24 (55.8%) had fecal samples recovered within the first 3 days of clinical presentation. Fecal miRNA-223 (10.5 fold), miR-451a (4.5 fold), and calprotectin (2.1 fold) concentrations were significant higher in NEC compared with the non-NEC group (p < 0.009). Accepting a minimum sensitivity of 0.75, the positive predictive values (PPVs) ranged between 0.19 and 0.20. Combining fecal biomarkers and CRP (Day 1) could marginally increase the PPVs (0.31–0.34) but adversely lowered the sensitivity (0.54–0.63). Conclusions: Although fecal miRNA biomarkers and calprotectin concentrations were significantly higher in the NEC group, the considerable overlapping of concentrations between groups and low recovery of stool specimens within 72 h of clinical presentation rendered fecal noninvasive tests of limited clinical value in guiding diagnosis of NEC during the acute phase. A further study is underway to evaluate their roles in surveillance for predicting high-risk premature infants developing NEC.

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“…Compared to molecular markers such as methylation of SEPT9 [19,65,66] in tumor-derived cell-free DNA, microRNA signatures in various biofluids (plasma, serum, or stool) [67][68][69], genetic [70,71], or proteomic markers [72][73][74] performance of methylation markers in stool DNA for detecting various stages of CRC seems poorer. In the reviewed studies, methylation of several genes was associated with increased risk of NAA/AA/Ad, early and late stages of CRC, supporting a role of DNA methylation at all stages of CRC, and suggesting potential use of these biomarkers for risk stratification in CRC screening.…”

Section: Discussionmentioning

confidence: 99%

Fecal DNA methylation markers for detecting stages of colorectal cancer and its precursors: a systematic review

et al. 2020

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Background: DNA methylation biomarkers in stool may have applications in early colorectal cancer (CRC) detection; however, their association with stages of CRC carcinogenesis or their performance in detecting various stages is unclear. We aimed to systematically review the evidence for DNA methylation markers in stool for risk stratification or detection of specific CRC stages, as well as precursors of CRC. Methods: We conducted a systematic search in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched PubMed and ISI Web of Knowledge to identify relevant studies published until 14th January 2020. Two reviewers independently extracted data on study population characteristics, candidate genes, methylation measurement methods, odds ratios (ORs), overall and stage-specific sensitivities, specificities, areas under the receiver operating characteristics curve, and p-values for statistical significance for OR and for association of methylation levels with stage. Results: Twenty-seven studies that reported stage-specific associations or performances of fecal DNA methylation markers for detecting colorectal neoplasms were identified. All studies used methylation-specific polymerase chain reaction for assessing methylation levels in the promoter or exon 1 regions of targeted genes. However, most studies were underpowered and limited by their case-control design. Furthermore, the stage-specific associations or sensitivities were validated for two markers (hypermethylation of GATA4 and VIM) only. Conclusion: Methylation markers in stool may be useful for detection of CRC precursors or CRC staging, but promising candidate markers need to be validated in longitudinal studies on large screening populations, performing epigenome-wide analyses. Identification of stage-specific DNA methylation biomarkers in stool could boost current strategies towards early detection and enable different approaches to precision medicine for CRC.

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Identification and Validation of MicroRNA Profiles in Fecal Samples for Detection of Colorectal Cancer

Cited by 57 publications

References 40 publications

<p>MicroRNA-421 Inhibits Apoptosis by Downregulating Caspase-3 in Human Colorectal Cancer</p>

<p>MicroRNA-421 Inhibits Apoptosis by Downregulating Caspase-3 in Human Colorectal Cancer</p>

A Prospective Cohort Study of Fecal miR-223 and miR-451a as Noninvasive and Specific Biomarkers for Diagnosis of Necrotizing Enterocolitis in Preterm Infants

Fecal DNA methylation markers for detecting stages of colorectal cancer and its precursors: a systematic review

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