|Year : 2019 | Volume
| Issue : 2 | Page : 278-285
Role of miRNA in transformation from normal tissue to colorectal adenoma and cancer
Guangkuo Liu, Bingqing Li
Department of Gastroenterology, The Affiliated Hospital of Chengde Medical College, Chengde, Hebei, China
|Date of Web Publication||1-Apr-2019|
Prof. Bingqing Li
Department of Gastroenterology, The Affiliated Hospital of Chengde Medical College, 36 Nanyingzi St., Chengde 067000, Hebei
Source of Support: None, Conflict of Interest: None
Although many modalities can be used to prolong the remission of colorectal cancer (CRC), early diagnosis is essential to improve the therapeutic outcomes. The conventional ways of diagnosing and monitoring the progresses from adenoma to CRC are colonoscopy and fecal occult blood test (FOBT). However, colonoscopy is expensive and invasive; while the FOBT is not sensitive. miRNAs may be a new modality to monitor the transition from adenoma to CRC. We reviewed publications of miRNA profile differences from colorectal normal mucosa (NM) to adenoma, and to CRC and tried to find the roles of miRNA in these transitions. This review also highlighted the possibility of serum miRNAs as markers for monitoring these transitions. The miRNA profiles are different from normal colorectal mucosa to adenoma and to CRC. The miRNAs may have pro- or anti-CRC effects through oncogenes such as c-Met and KRAS. Others may interfere with the immune system. More interestingly, some miRNAs are continuously increased from NM to adenoma and to CRC; others, such as miRNA-30b, are consequently decreased. The literature shows that miRNAs are involved in the whole process of the colorectal carcinogenesis. The miRNAs may be the biomarkers in monitoring the transition from adenoma to CRC.
Keywords: Carcinogenesis, colorectal adenoma, colorectal cancer, miRNA, oncogene
|How to cite this article:|
Liu G, Li B. Role of miRNA in transformation from normal tissue to colorectal adenoma and cancer. J Can Res Ther 2019;15:278-85
| > Introduction|| |
It is estimated that colorectal cancer (CRC) is the third most common cancer and one of the main causes of cancer death worldwide. The intermediate phase from benign to cancer transformation is commonly adenoma polyps with the precancerous feature. The carcinogenesis of CRC needs 10 years. Early CRC needs about 2–5 years to develop from endoscopic recognizable adenomas,, which allows us to diagnose CRC in early phase if we have proper diagnostic facilities and therefore, improve the prognosis of these patients.
The conventional ways of monitoring the progresses of adenoma polyps are colonoscopy, fecal occult blood test (FOBT), fecal immunochemical test and some serum and stool biomarkers such as serum carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19,9), CYFRA 21-1, galanin, and trefoil factor 3 protein. However, these modalities are either invasive or not sensitive, physicians/scientists are still exploring a better method to monitor this transition.
Theoretically, cancers are rooted in molecular changes, and therefore, the CRC development is characterized by specific molecular signatures. The microRNA (now miRNA or miR) was discovered by Lee et al. However, miRNA was not recognized as a distinct class of biological regulator until the early 2000s. Since Its function is to regulate gene expression either by post-transcriptionally suppressing mRNA translation or by mRNA degradation which repress protein production, miRNAs are involved in many physiological processes and diseases, each individual miRNA may target hundreds of genes, and one mRNA may also be the target of multiple miRNAs. It was estimated that miRNA regulates up to one-third of the total human protein-coding genes. They also play important roles in cancer development, proliferation, regression, and metastasis. In 2003, miRNAs were first reported to be associated with CRC. Our recent study demonstrated that the expression of Has-miR-182-5p in CRC tissue is increased, and the expression is correlated with the cancer stage and prognosis. miRNAs functions as tumor suppressors or oncogenes depending on the characteristics of their downstream targets. There is a well-known theory: the CRC is developed from normal mucosa (NM) to adenocarcinoma through adenoma, so-called nonneoplastic mucosa-adenoma-adenocarcinoma pathway that provides an opportunity to determine alterations during tumorigenesis. The present review was to analyze the role of miRNA in the transformation from benign diseases to malignancy in the colorectum.
| > The Mirna Profile Changes from Benign to Adenoma With Precancerous Feature and to Colorectal Cancer|| |
It should be clearly aware that most small adenomatous colon polyps never progress to cancer. The stepwise progress from NM to adenoma polyp to cancer as described in this section happens in some of the CRC patients. We tried to emphasize the role of miRNA in the carcinogenesis of CRC.
miRNA expression profiling offers new insights into better understanding and identifying differences between benign adenoma and more clinically aggressive adenoma, and into tumorigenesis. miRNA is helpful for patient risk stratification.
Microarrays are the technology to evaluate the miRNA profile changes from benign to adenoma with precancerous feature and to CRC because this technology enables thousands of genes to be tested simultaneously for differential expression between two or more biological conditions.
Many studies found that the miRNA profiles from normal controls, patients with colorectal adenoma and CRC are significantly different., Using miRNA microarray, Slattery et al. examined the miRNA profile of paraffin-embedded colorectal tissue samples from normal controls, patients with colorectal adenoma and CRC and found that the miRNA profiles are significantly different between the tissues from different patients and normal controls. First, the number of miRNA expression is different: Of the 2006 miRNAs on the Agilent Microarray platform, 36.74% were not expressed in normal colonic mucosa. 46.56% were not expressed in adenoma tissue and 36.29% were not expressed in cancer tissue. Furthermore, the expressed miRNAs among the three groups were not consistent. In comparison to NM, close to 2/3 of miRNAs were downregulated in CRC; another microarray analysis showed that among 18 differentially expressed miRNAs, 8 were upregulated and 10 were downregulated in the serum of the CRC patients compared with the healthy controls.
Nagy et al. examined the miRNA profile and found that the tissue miRNA 18a, 18b, 431, 503, 1246, and 4417 are continuously increased from normal tissue to adenoma to CRC, while others, such as miRNA 133a, 375, 378, 422 and 479 are consecutively decreased from NM to adenoma and to CRC. Uratani et al. found that the expressions of miRNA-21, miRNA-29a, miRNA-92a, and miRNA-135b are significantly higher in CRC. Furthermore, three of them (miRNA-21, miRNA-92a, and miRNA-135b) are significantly overexpressed in the tissues of colorectal adenomas compared with normal colonic mucosa [Figure 1]. Moreover, the serum levels of miR-21, miR-29a, and miR-92a are significantly higher in patients with adenomas compared with those in healthy controls and there is a positive relationship between these three miRNA and adenoma size and total adenoma number within the colorectum. Uratani's study implies that miRNA-21, miRNA-29a, miRNA-92a, and miRNA-135b are involved in the transformation from NM to adenoma and to CRC.
|Figure 1: MiRNAs expression levels in tissue specimens during normal-adenoma-carcinoma sequence. (a) miR-21, (b) miR-29a, (c) miR-92a, and (d) miR-135b. The y-axis (log10 scale) represents relative expression of miRNAs normalized to miR-16 in normal colonic mucosa (NCM; n = 20), adenomatous polyps (AD; n = 27) and colorectal cancer ( colorectal cancer; n = 19) tissues (*P < 0.05; ***P < 0.001)|
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Tsikitis et al. also performed microarrays in paraffin-embedded specimens obtained from subjects with NM, hyperplastic polyps, tubular adenomas (TA), tubulovillous adenomas or high-grade dysplasia (TVHG), and serrated polyps. They found that 99 miRNAs have clear distribution among these five histopathologic groups which implies that specific histologic entity has specific miRNA profile. They further conducted 10 pairwise comparisons and found that the most significant differences of miRNAs are between TVHG and other histological groups: 47 miRNAs are differentially expressed between TVHG and HPNM; 25 miRNAs between TVHG and sessile serrated adenoma/polyps and 45 miRNAs between TVHG and TA. The topmost upregulated miRNA in HPNM are miRNA-145,-143,-107,-194, and-26a in comparison of TA, TVHG dysplasia and the top downregulated miRNA are miRNA-663,-1268,-320b,-1275, and -320b. miRNA-145 and miRNA-619 help to discriminate lower risk polys from higher risk polyps. Another important finding of Tsikikis study is that miRNA-143/145 and -30a significantly downregulated in more advanced adenoma of cancer-free individuals. This is significant because these three miRNAs are significantly decreased in foci of high-grade dysplasia adjacent to invasive disease and moreover, significantly downregulated in CRC. These connections imply that miRNAs play a role in the transformation from benign polyps to adenoma to high-grade dysplasia and finally, to CRC.
Bartley et al. examined 21 patients with colorectal adenocarcinoma which was developed from a pre-existing adenoma, they profiled 866 miRNAs and found that 230 are significantly differentially expressed during the longitudinal process. They divided the histology into 4 stages: nonneoplastic mucosa; low-grade dysplasia in adenoma; high-grade dysplasia in adenoma and adenocarcinoma. They found that 216 of the 230 miRNAs are differentially expressed between nonneoplastic mucosa and adenocarcinoma, 144 are differentially expressed between nonneoplastic mucosa and high-grade dysplasia in adenomas, 134 from nonneoplastic mucosa to low-grade dysplasia, 99 between low-grade dysplasia and adenocarcinoma, 25 from high-grade dysplasia to adenocarcinoma, and 3 between low-grade and high-grade dysplasia. Thirty-six miRNAs are significantly differentially expressed along the entire sequence.
Further analysis revealed that among the 230 miRNAs that are differentially expressed, 134 show early altered expressions, from nonneoplastic mucosa to low-grade dysplasia in adenoma; 96 are later alteration of expression. Thirty-three are altered in the mid portion of the nonneoplastic mucosa-adenoma-adenocarcinoma and 63 at the step of adenocarcinoma.
Yin et al. performed microarray in normal colorectal tissues, colorectal adenomas and CRC tissues and aimed to screen differentially expressed miRNAs during colorectal tumorigenesis. They found that specific histologic entity has specific miRNA profile, which is consistent with Tsikitis's study. Among the 67 miRNAs dysregulated in CRC tumorigenesis, 28 are continually changing from normal to adenoma to CRC; 8 (miR-18a, miR-18b, miR-31, miR-142-5p, miR-145, miR-212, miR-451, and miR-638) have relatively higher or lower fold changes in colorectal tissues. Five miRNAs (miR-18a, miR-18b, miR-31, miR-142-5p, and miR-212) have >1.72-fold (compared to normal) increase in adenoma tissues and the expressions are continuously increased in CRC tissues; three (miR-145, miR-451, and miR-638) are significantly downregulated to at least 0.69-fold (compared to normal) in adenoma tissues and these expressions are further decreased in CRC tissue. These data suggested that deregulation of the eight miRNAs may play essential roles in CRC tumorigenesis. Other studies were summarized in [Table 1]. In summary, some of the studies found that many miRNAs are different among NM, adenoma, and CRC. Although the profiles from different study are inconsistent, one thing is clear, following the accumulation of the pertinent publications, the value of the profile change will be clarified.
| > The Role of Mirna in Carcinogenesis of Colorectal Cancer|| |
It is well known that the miRNA-320 family inhibits cell proliferation. Tadano et al. found via microarray that the miRNA-320 family, including miRNA-320a, miRNA-320b, miRNA-320c, miRNA-320d, and miRNA-320e are downregulated in colorectal adenoma and submucosal invasive carcinoma tissues. This implied that miRNA may be involved in carcinogenesis. Many documentations demonstrated that miRNA is involved in colorectal carcinogenesis through different mechanisms such as oncogenic pathways, immune surveillance, interfere tight junction, and cell division.
CDK6 expression was found to be increased longitudinally from nonneoplastic mucosa through adenoma to submucosal invasive carcinoma tissues. CDK6 shows an inverse correlation with miRNA-320 family expression. To reveal the role of the miRNA-320 family in CRC, the authors transfected colorectal cell lines (SW480) with miRNA-320 family, the Cell Proliferation Assay showed that the over-expressions of miRNA-320a, 320b, 320c, or 320d significantly inhibit the SW480 cell growth. The authors further demonstrated that the target gene of miRNA-320 family is CDK6, a cyclin-D1-dependent kinase. CDK6 plays an important role in G1/S phase transition in the cell cycle and therefore, plays an important role in CRC carcinogenesis. Colorectal cell line (HT29 and SW480) studies showed that both mRNA and protein levels of CDK6 are significantly suppressed when transfected with miRNA-320 family mimics.
RAS is a GTPase. The mutation of a RAS gene is an essential step in the development of many cancers. Activating RAS mutation is the most prevalent oncogenic driver in CRC development. The oncogenic RAS mutation occurs in enlarging colon adenomas to initiate CRC. Le Rolle et al. demonstrated the pathway from pre-malignant adenoma to CRC: KRAS mutation-embryonic stem cell-like transition-colorectal carcinoma.
The activity of KRAS is decreased when mutated which causes the accumulation of the active GTP-bound proteins, such as RhoA, which results in sustained signaling of downstream pathways and sustained cell proliferation. Le Rolle's et al. study demonstrated that KRAS mutation elicits the embryonic stem cell-like program which initiates the transition from colon adenoma to Stage I carcinoma. miRNA145 is an embryonic stem cell program inhibitor which promotes the cell differentiation and therefore, suppresses the transformation of cells harbored with mutated KRAS gene from adenoma to CRC. miR-145 inhibits the proliferation of SW48 cells harbored with mutated KRAS gene.
Another target of miRNA is RAS p21 GTPase activating protein 1 (RASA1). It is well known that RASA1 and its downstream proteins play crucial roles in the regulation of cellular growth and differentiation, down-regulation of RASA1 increases cell proliferation. Sun et al. infected human colorectal adenocarcinoma cells (HT-29) with pre-miRNA-31 precursor and found that miRNA-31 significantly decreased RASA1 expression. miRNA-31, via inhibition of RASA1, enhances CRC cell growth and therefore, plays a significant role in tumorigenesis. Chen et al. investigated the relationship between miRNA-137 and adenoma-CRC, they found that miRNA-137 is significantly down-regulated in both adenoma and CRC tissues.In vitro study showed that over expression of miRNA-137 inhibits CRC cell proliferation, colony formation, migration, and invasion. They further confirmed that miR-137 suppresses oncogene c-Met expression. Other miRNAs such as miRNA-145, miRNA-212, and miRNA-638 also involved in colorectal tumorigenesis.
It is well known that mutations and overexpression of Wnt/β-catenin are associated with many cancers including CRC., Bartley et al. compared the miRNA alteration patterns to nuclear β-catenin localization and found that the β-catenin immunohistostaining is negative in the nuclear of nonneoplastic mucosa; nearly 3.8% of low-grade dysplasia in adenomas; 7.1% of high-grade dysplasia in adenomas, and 9.1% of adenocarcinomas. All the data indicated that the alteration of miRNA expression preceded major nuclear localization of β-catenin. Furthermore, there is correlation between the levels of nuclear β-catenin and 23 miRNAs, 13 were positively correlated and 10 inversely correlated. These imply that miRNAs are in the driver seat and it is the miRNA that initiated the process of nonneoplastic mucosa-adenoma-adenocarcinoma pathway.
Another miRNA that participated in carcinogenesis is miRNA-27a. It is well known that besides gene mutations and epigenetic modifications, the impairment of immune surveillance also plays an important role. Tumor cells stimulate innate and adaptive immune responses which include the activation of cytotoxic T-cells. The normal function of antigen processing and presentation by major histocompatibility complex (MHC) Class I molecules is critical to the immune response. Cancer cells produce antigens which are bound to Class I MHC molecules and brought to the surface of the cell by the class I MHC molecule. Most cytotoxic T-cells express T-cell receptors that can recognize a specific antigen such as Class I MHC-bound tumor antigen. When recognized, T-cell destroys tumor cells. Colangelo et al. found that miRNA-27a is upregulated in adenoma and further increases during the evolution to adenocarcinoma. Calreticulin is a calcium-binding chaperone that plays important roles in the immune response. Calreticulin facilitates the folding of MHC class I molecules and influences antigen presentation to cytotoxic T-cells. miRNA-27a directly targets Calreticulin and impacts tumor antigen processing and presentation and interferes the recognition by cytotoxic T-cells. miRNA-27a, therefore, acts as an oncomiRNA, inhibits MHC Class I expression via calreticulin downregulation and affects tumor progression.
Tight junction protein 1 (TJP1) is a cell migration-related gene and plays an essential role in maintaining cell to cell integrity. Loss of TJP1 leads to cancer cell invasion and tumor metastasis., Yin et al. found that the miRNA-212 is increased in colorectal adenoma and cancer, TJP1 is a direct target of miRNA-212 and therefore, miRNA-212/TJP1 signaling plays an important role in colorectal adenoma-carcinoma transition.
Cell division control protein 42 homolog (CDC42) is a protein involved in regulation of the cell cycle (G1 to S phase transition). CDC42 is an important regulator of cytoskeletal remodeling, cell cycle progression, cell proliferation, survival, and migration. CDC42 is increased in many human cancers including CRC. CDC42 activation is crucial in the progression and its level is positively correlated with poor differentiation of CRC. Humphreys et al. studied the relationship between miRNA-18a and CDC42. They first demonstrated that miRNA-18a has lower expression than other miRNA-17-92 cluster members (miRNA-17, miRNA-19a, miRNA-19b, miRNA-20a, and miRNA-92a) in CRC compared with matched normal samples. They transfected miRNA-18a mimics to CRC cell line (HCT116) and demonstrated that miRNA-18a decreases CDC42 on both message RNA and protein levels. In parallel with CDC42 effects, miRNA-18a inhibits CRC cell proliferation, decreases migration, increases apoptosis and induces cell cycle arrest.
| > Mirnas as Cancer Markers|| |
The value of stool miRNAs on monitoring the transformation from adenoma to colorectal cancer
It is well known that the current CRC screening modalities include FOBT and endoscopy (sigmoidoscopy and colonoscopy). However, FOBT is not sensitive; endoscopy is invasive, expensive and needs expertise to detect the precancerous and cancerous lesions. Furthermore, around 9% of CRCs occur in individuals within 3 years of a screening colonoscopy. This implies that these patients must be monitored, and endoscopy has to be repeated in 3 years which increases the expenses. More affordable, noninvasive or less invasive, more sensitive and more compliant modalities are needed to monitor the transformation from adenoma to CRC. Physicians kept trying to find the biomarker of CRC for many years. CEA and CA19-9 have been used in practice for many years. However, the accuracy (area under receiver operating characteristic curve, area under the curve [AUC]) was poor (0.789 for CEA, 0.690 for CA 19-9). Some author even doubts the value in CRC diagnosis.
Theoretically, stool miRNAs are promising method in monitoring CRC tumorigenesis: They are easy to obtain and not invasive. Stool miRNA changes from normal to adenoma to colorectal carcinoma are theoretically exist because the stool has mucosa contents exfoliated from colorectum. Using microarray and then PCR, Ahmed et al. found that the expressions of 12 miRNAs (miR-7, miR-17, miR-20a, miR-21, miR-92a, miR-96, miR-106a, miR-134, miR-183, miR-196a, miR-199a-3p, and miR214) were significantly increased in the stool of patients with colon cancer; furthermore, these expressions are more pronounced in patients with later tumor-lymph node-metastatic (TNM) carcinoma stages compared with those with adenomas. Another interesting finding is, 8 miRNAs (miR-9, miR-29b, miR-127-5p, miR-138, miR-143, miR-146a, miR-222 and miR-938) are significantly decreased in the stool of patients with colon cancer, which are also more pronounced from early to later TNM stages. They also demonstrated that the pattern of miRNAs in stool is similar to mucosal tissues. Yau et al. investigated the relationship between stool miR-20a and CRC and found that stool miR-20a content is significantly higher in patients with CRC tumors compared to that in those from controls. The sensitivity of stool miR-20a to diagnose CRC is 55% and specificity is 82%. Yau concluded that miR-20a can be utilized as a potential noninvasive biomarker for CRC screening. Link et al. compared the fecal miRNAs among normal control, nonadvanced adenoma, advanced adenoma and CRC. They found that compared with individuals free of colorectal neoplasia, the expressions of miR-21 and miR-106a are significantly higher in patients with adenomas and CRCs. However, there is no significant difference between patients with adenoma and those with CRC. Wu et al. measured miR-21, miR-92a, and miR-135b in stool samples of normal control, patients with CRC or polyps and found that these three miRNAs are consecutively increased from normal control to patients with polyps and to those with CRC. However, the sensitivity of miR-92a for CRC is 71.6% and the specificity is 73.3%; the sensitivity of stool miR-135b for CRC is 78%, for advanced adenoma is 73% and the specificity is 68%. One thing needed to be clear is that stool miRNA is just useful for stratification of the patients. Endoscopy is an immediate clinical need for further evaluation to those whose miRNA profiles indicate high risk of CRC. miRNA might be helpful to avoid unnecessary colonoscopy for patients with lower risk of CRC.
| > The Value of Serum Mirnas on Monitoring the Transformation from Adenoma to Colorectal Cancer|| |
Theoretically, serum miRNAs are promising method in monitoring CRC tumorigenesis: They are easy to obtain, minimally invasive and stable. Many recent studies demonstrated that serum miRNAs can potentially identify various types of cancer, such as lung, prostate, breast, ovarian, and liver cancer. Wang et al. analyzed the diagnostic value of miRNA in CRC and found that the combination of six miRNAs (miR-21, let-7 g, miR-31, miR-92a, miR-181b, and miR-203) had high sensitivity and specificity for differentiation of the CRC patients from cancer-free controls. The diagnostic accuracy (AUC) >0.90 and reached the “excellent” level (0.50-0.60 = fail, 0.60–0.70 = poor, 0.70–0.80 = fair, 0.80–0.90 = good, 0.90–1 = excellent). Using the same samples to test the accuracy of CEA and CA 19-9, they found that the AUC were only 0.65 and 0.60, respectively (poor accuracy).
The role of miRNA in CRC diagnosis seems more confirmative. It is essential to monitor the transition from adenoma to CRC and therefore, to decide the therapeutic modality before the transition or in early phase after transformation. Uratani et al. observed the expression of four miRNAs, miR-21, miR-29a, miR-92a, and miR-135b, they found that three of them (miR-21, miR-92a, and miR-135b) are significantly higher in colorectal adenomas compared with NM. They further tested the serum expressions of these four miRNAs and found that the serum expressions of miR-21, miR-29a and miR-92a are significantly higher in patients with adenomas compared with healthy controls. Moreover, these serum miRNA levels are significantly correlated with the size and total number of adenoma within the colorectum. The accuracy analysis showed that in differentiation of patients with advanced adenomas from healthy controls, the accuracy (AUC) of the serum miRNA-21 is 0.866; serum miRNA-29a is 0.851 and serum miRNA-92a is 0.839.
Another interesting study by Ho et al. also compared the miRNA changes in the progression from normal controls to nonadvanced adenoma to advanced adenoma and to CRC. They found that both serum miRNA-30b (negatively) and miRNA-486 (positively) are correlated with the severity of colorectal neoplasia.
The current publications support the notion that serum miRNA is a less invasive, easy to perform, cheap, and more compliant modality in monitoring the transition and diagnosing CRC. Although most studies found that up-regulations or down-regulations of some of the serum miRNAs are related to adenoma and CRC, majority of these studies are not repeatable. However, miRNA-21,, and miRNA-29a,, are indeed repeatable in several studies. The reliability and sensitivity need further study. The promising data imply that miRNA will be more valuable in monitoring the transition from adenoma to CRC and in diagnosing earlier CRC compared with the current serum markers such as CEA, CA19-9, and CA125. The limitation of circulating miRNA is that some miRNAs may universally dysregulated in many types of cancers and therefore, serum miRNA may not be specific for CRC diagnosis.
| > Possible Therapeutic Application of Mirna in the Transition from Colorectal Adenoma to Colorectal Cancer|| |
The application of miRNA to the treatment of CRC are currently limited in cell lines,,, and animal models. There is no report on the treatment of adenoma using miRNA in patients.
The therapeutic effects of miRNA on CRC in human colorectal tumorigenesis may shed light on new strategies for future colorectal tumor therapy. However, the functions of miRNAs are very complicated, they play important roles in many physiological and disease processes, not only a single miRNA may target hundreds of genes but also one mRNA may be targeted by multiple miRNAs. Therefore, more specific miRNA is needed in cancer treatment. Theoretically, it is not easy to avoid the side effect(s) if the miRNA is not specific. There is a long way to go before the clinical application. Still, we hope that miRNA-based therapeutics will become a reality in clinical practice in the future.
| > Conclusion|| |
The miRNA profiles are different between NM and adenoma and CRC in colorectum. Some of the miRNAs are upregulated in neoplasia and others are downregulated. The miRNAs regulate cancer cell proliferation, migration and invasion via oncogenes such as c-Met and KRAS. Some of the miRNAs are released from colorectal adenoma or CRC to circulation which provides a tool to monitor the transition from benign lesion to malignancy.
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Conflicts of interest
There are no conflicts of interest.
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