|Ahead of print publication
Plasma miR-183-5p in colorectal cancer patients as potential predictive lymph node metastasis marker
Fatemeh Sanjabi1, Reza Nekouian2, Abolfazl Akbari3, Rezvan Mirzaei3, Azam Fattahi4
1 Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
2 Pediatric Growth and Development Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran
3 Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
4 Center for Research and Training in Skin Disease and Leprosy, Tehran University of Medical Sciences, Tehran, Iran
|Date of Submission||13-Feb-2020|
|Date of Decision||30-May-2020|
|Date of Acceptance||12-Aug-2020|
|Date of Web Publication||03-Aug-2021|
Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical Sciences, Tehran; Pediatric Growth and Development Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran
Source of Support: None, Conflict of Interest: None
Background: Lymph node metastasis (LNM) is a point that often, treatment is not effective in colorectal cancer (CRC). Clinical and pathologic markers of prognosis help clinicians in selecting patients for adjuvant therapy after surgical resection in CRC. MiR-183-5p has been demonstrated to play as an oncogene in CRC, although its biological role still remains unclear. The aim of this study was to evaluate the expression of miR-183-5p in CRC and its potential relevance to clinicopathological characteristics as a prognostic biomarker.
Materials and Methods: In this case–control study, 33 CRC plasma samples at stage I-II-III, as well as plasma samples from 13 healthy controls, were collected. The relative expression levels of miR-183-5p in cancer and the normal samples were measured by quantitative real-time PCR. We analyzed their correlation with clinicopathological parameters and prognostic value.
Results: Our results indicated that miR-183-5p was significantly overexpressed in CRC samples compared to healthy controls (P < 0.001) from a cutoff value of 3.9 with a sensitivity of 89% and a specificity of 91% and an AUC value of 0.74. Further analysis showed that a high plasma expression level of miR-183-5p was significantly associated with LNM and higher tumor/node/metastases stage (III) (P-value < 0.001).
Conclusion: In conclusion, the overexpression of miR-183-5p is highly related to advanced clinical stage, LNM and poor prognosis of CRC, indicating that miR-183-5p may serve as a predictive biomarker for the prognosis or the aggressiveness of CRC.
Keywords: Biomarker, colorectal cancer, lymph/node/metastasis, mir-183, plasma
|How to cite this URL:|
Sanjabi F, Nekouian R, Akbari A, Mirzaei R, Fattahi A. Plasma miR-183-5p in colorectal cancer patients as potential predictive lymph node metastasis marker. J Can Res Ther [Epub ahead of print] [cited 2021 Dec 5]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=322901
| > Introduction|| |
Colorectal cancer (CRC) is considered as one of the most diagnosed gastrointestinal malignancy in the world. It is largely asymptomatic until the latter stages, often times when cancer has metastasized. Therefore, CRC continues to be an extremely poor prognosis cancer. The main prognostic factors for CRC remain tumor/node/metastases (TNM) staging system validated by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC). Lymph/node/metastasis (LNM), as a decisive variable of the AJCC/UICC TNM system, notifies prognosis and is a vital factor in determining supplementary administration, particularly adjuvant chemotherapy. Although segmental resection is still the best treatment strategy for CRC patients, tumor relapse after either local or distant resection increasing the risk of cancer-related death. Recent researches have been showed that patients with early stages (negative lymph nodes) have 5-year survival rates of approximately 70%–80% in comparison with advanced stages (positive lymph nodes) about 30%–70%. Accordingly, the development of novel noninvasive biomarkers, which could serve as a predictive biomarker for the prognosis or the aggressiveness of CRC is an urgent need for optimal treatments. Compelling evidence have demonstrated that MicroRNA (miRNA) levels are remarkably stable either in serum or plasma, making them a suitable candidate for blood-based biomarker investigations., miRNAs, as small noncoding RNAs comprised about 18–25 nucleotides, regulate gene expression at the posttranscriptional level by binding to the 3′ untranslated regions of target messenger RNAs., Dysregulation of miRNAs and correlation with clinicopathological features of tumors have frequently been reported for several cancers. A growing number of evidence indicated that these noncoding RNAs could potentially be used as either diagnostic or prognostic biomarkers for CRC., MiR-183-5p has been illustrated to play pleomorphic functional roles in different tumors. In most tumor types, miR-183-5p is highly expressed and promotes tumorigenesis, cancer progression, and metastasis; yet tumor-suppressive effects have also been reported in some tumors. For instance, it has a potential oncogenic role in CRC progression and metastasis by contributing to the down-regulation of two important tumor suppressor genes in CRC signaling pathway, EGR1, and PTEN. Also, further studies have revealed the function of miR-183-5p as an oncogene in breast cancer, lung cancer, and hepatocellular carcinoma.,, However, other studies showed that miR-183-5p was downregulated in tumors like cervical, signifying its tumor suppression role in inhibiting the invasion of these cancer cells. The study was aimed to examine the plasma expression of miR-183-5p in concordance with clinicopathological characteristics, to evaluate whether there was a correlation between its expression and the lymph node metastasis (LNM) in CRC patients.
| > Materials and Methods|| |
Clinicopathological characteristics of the studied colorectal cancer patients
Pre-surgery plasma miRNAs were analyzed using the plasma samples from a total number of 33 CRC patients with neither history of chemotherapy nor treatment in two past months before the start point of the study. The study was approved in the Ethics Committee of Iran University of Medical Sciences (Ethical code: IR. IUMS. REC 1395.9413522003). The study population included 19 male and 14 female patients, with the age group of 37–83 years (mean 59 ± 2.3 years). Thirteen individuals subjected to CRC screening with normal colonoscopy and no current malignancy or any history of Irritable Bowel Syndrome, Inflammatory bowel disease were included as normal population which comprised 7 males, and 6 females, with the age group of 35–81 years (mean 58 ± 2.6 years). For better optimization and understanding, the age group of healthy controls was matched to the cancer patients. The staging of CRC patients was based on (TNM) staging of UICC/AJCC. According to postsurgery pathological examination, patients were stratified as follows: 17 patients (51.5%) in Stage I/II category and 16 patients (48.5%) were in stage III. The characteristics and clinical features of patients are summarized in [Table 1].
Sample collection and preparation
Peripheral blood was collected in Vacutainer liquid EDTA 6 ml blood collection tubes, and plasma fractions were separated by density gradient separation at 2000 g for 10 min at 4°C followed by 12,000 g for 10 min at 4°C, Plasma samples were stored in 1.5 ml DNase/RNase free microtubes and frozen a −80°C until RNA extraction.
Total RNA was extracted from 200 μl plasma using TRIzol LS reagent (Gipco, USA) according to the manufacturer's protocol. Briefly, 1000 μl TRIzol LS reagent was added to 200 μl plasma samples, after phase separation by 200 μl chloroform addition and centrifugation at 12,000 g for 15 min. Then, 600 μl isopropanol was added to the aqueous phase and centrifuged to precipitate RNA. RNA pellet was washed by 75% ethanol and air-dried for 5 min, and the final elution volume was made up to 12 μl. The concentrations of all samples were quantified by NanoDrop OneC Spectrophotometer (Thermo Scientific, USA).
Reverse transcription and real-time quantitative polymerase chain reaction
500 ng total RNA from each sample was reversely transcribed to cDNA, using Prime Script RT reagent Kit (Takara, Japan, cat # RR037Q) according to the manufacturer's instruction. The cDNA product was stored at − 20°C for further analysis. MiRNA expression was quantified by reverse transcription and real-time quantitative polymerase chain reaction in a final volume of 20 μl with Roche Light cycler 96 (Roche, Germany) using miScript SYBR Green PCR Kit (Qiagen, USA, cat # 218073). Each reaction contained 10 μl SYBR Green reagents, 1 μl specific forward and reverse primer, and 8 μl DEPC-treated water. The amplification reaction was completed by the following conditions: 95°C for 5 min, followed by 45 cycles at 95°C for 10 s and 60°C for 60 s. Specific stem-loop primers were designed for miR-183-5p and RNA U6 (internal control). The miRNA-specific forward primers were designed according to the miRNA sequence obtained from the miRBase database (http://microrna.sanger.ac.uk/). The specific reverse primer was also designed by oligo3 software. No-template controls for both miRNAs were included on each strip to ensure target-specific amplification, and all real-time PCR reactions were carried out in duplicate. To validate the specificity of the target PCR products, melting curve analysis was performed at the end of PCR cycles. The expression levels of miRNAs were normalized to RNA U6 as a reference gene. The relative amounts of target miRNAs to RNA U6 was calculated using the equation 2−ΔCt, where ΔCt = (Cttarget–Ctinternal control). Furthermore, the efficacy of primers was examined through linear regression (LinReg) software.
The statistical analysis was performed using IBM SPSS Statistics, Version 22.0. Armonk, NY: IBM Corp; 2013. The Kolmogorov–Smirnov test was applied to assess the normal distribution. The Mann–Whitney U test was used to determine the differences of miRNA expression between CRC patients and controls. In addition, the Kruskall–Wallis test was used to analyze the relationship between the differential expression of miRNAs and clinicopathological characteristics. Receiver operating characteristic (ROC) curve analysis was used to evaluate the potential diagnostic value. P values < 0.05 were considered statistically significant, and all P values were two-sided.
| > Results|| |
First, the dependence of plasma miRNA expression levels from the demographic characteristics of CRC patients was investigated. No direct correlations between age or gender and levels of any of the tested miRNAs were found [Figure 1].
|Figure 1: MicroRNA expression according to age and sex. Box plots of relative MicroRNA expression levels in plasma of colorectal cancer patients (a) between two age groups: <55 years, >55 years (P = 0.43). (b) between genders (P = 0.87). The expression levels of MicroRNAs were normalized to RNA U6|
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To identify the connections between clinicopathological characteristics and expression levels of miR-183-5p, we investigated the relationships of plasma expression levels of miR-183-5p in a different stage of CRC with healthy control samples using Kruskal–Wallis test. No interrelation between stage I/II and controls have been found (P = 0.81). However, there was a statistically significant connection between the plasma level of miR-183-5p in Stage III and normal samples (P < 0.001) [Figure 2]a. In addition, miR-183-5p exhibited a sharp relation between Stage I/II and III (P < 0.001). We also examined relative miR-183-5p expression levels in ascending, descending, and rectum, but we showed no significant relation between different locations and plasma levels of miR-183-5p [Figure 2]b.
|Figure 2: MicroRNA expression in plasma. Box plots of relative miR-183-5p expression levels (a) in plasma of colorectal cancer patients and healthy individuals. (b) In different location of colon and rectum. The expression levels of MicroRNAs were normalized to RNA U6|
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Receiver operating characteristic value of the plasma miR-183-5p for a. colorectal cancer patients versus healthy controls and b. colorectal cancer patients between Stage I/II and III
We performed ROC curve analysis to evaluate the diagnostic value of plasma-circulating miR-183-5p. We identified a cut-off value that distinguished 33 CRC patients from 13 healthy sex-and age-matched controls. The ROC curve data showed that miR-183-5p could distinguish the CRC patients from the controls. The plasma level of miR-183-5p had a sensitivity of 89.0% and a specificity of 91.0% to differentiate the CRC patients from the healthy controls, with an AUC of 0.948 at the optimal cutoff point (P < 0.0001, 95% confidence interval [CI]: (0.823-0.957) [Figure 3]a. Furthermore, we examined the diagnostic value of miR-183-5p between CRC patients with stage I/II and stage III to evaluate the potential prognostic power of miR-183-5p for predicting LNM. The ROC curve assessment revealed 92% specificity and 79% sensitivity with an AUC of 0.918 at the optimal cut-off point (P < 0.0001, 95% CI: (0.766-0.956) [Figure 3]b.
|Figure 3: (a) Receiver operating characteristic curve to assess the value of plasma miR-183 in colorectal cancer patients compared to 13 healthy controls (P < 0.0001). (b) Receiver operating characteristic curve assessment of miR-183 between colorectal cancer patients with Stage I/II and Stage III (P < 0.0001)|
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| > Discussion|| |
Identification of reliable biomarkers for prognosis remains a major challenge in cancer research, especially for CRC. Based on data mining from previous studies of miRNAs in CRC, we focused on the values of relative expression of miR-183 for serving as a useful biomarker in the prediction of LNM. According to recent researches, LNM is not only a key prognostic factor for patients dealing with CRC, but also is a risk factor for recurrence and distant metastasis. In fact, the higher the number of positive lymph nodes detected, the poorer the prognosis would it be. Hence, in the colorectal TNM staging system, the node status was applied as the parameter to determine the stage III tumors from the stage II lesions. Accordingly, finding the noninvasive prognostic biomarkers has been considered as an urgent need in LNM management.
Although many studies have evaluated the diagnostic potential of circulating miRNAs in CRC patients, few have explored their prognostic potential.,,, We examine the sensitivity and specificity of plasma miR-183-5p between node-negative and node-positive CRC patients to evaluate the possibility of its clinical value as a prognostic biomarker. Our results showed that the expression of plasma miR-183-5p was upregulated significantly in CRC patients in comparison with normal controls. Furthermore, our findings revealed that the miR-183-5p expression in plasma was significantly associated with LNM and TNM stage. The ROC curve analyses revealed a potential diagnostic value of the miR-183-5p between stage I/II and III with an AUC of 0.918 (92% specificity and 79% sensitivity). Compared with previous researches, most importantly, our results established the potential of miR-183-5p as a prognostic biomarker in the prediction of LNM in CRC.
Several studies have reported the utility of unique miRNA profiling in the diagnosis of numerous malignancies and the prediction of prognosis. Furthermore, many reports have indicated that miRNA levels are remarkably stable either in serum or plasma, making them a suitable candidate for blood-based biomarker investigations. As a result, miRNAs receive widespread attention on their potential role in early diagnosis and prognosis of human cancers.
Since the development of the next-generation sequencing technique, many miRNAs such as mir-183 have been identified to be differentially expressed in different cancers, including CRC, which perhaps indicated their important functional significance. A large number of cancer cells demonstrate the high-expression of miR-183 being associated with poor clinical prognosis in CRC, breast cancer, hepatocellular cancer.,, There are several upstream regulators for miR-183, including signaling pathways and long noncoding RNAs (LNCs). Wnt/beta-catenin (CTNNB1) signaling pathway is the most studied regulatory pathway on mir-183, having a direct interaction on the upstream promoter region of miR-183. Activated CTNNB1 can upregulate the expression of miR-183 and also reduction of CTNNB1 may contribute to downregulations of miR-183. Moreover, IncRNAs show a crucial role in regulating the expression of miRNA as well. For instance, IncRNA MALAT1 plays as a competitive endogenous RNA for miR-183 that inhibits the expression and function of miR-183. The potential downstream targets of miR-183 include oncogenes, antioncogenes, cell signal transduction molecules, cell cycle regulation genes, and molecules related to invasion and metastasis. miR-183 can function as an anti-oncogene by inhibiting the expression of oncogene, inhibiting cell migration and invasion. It can also play an oncogenic role resulting in suppression of the antioncogene, expression that, in turn, promoting cell migration and invasion. miR-183 promotes tumor invasion and metastasis by targeting PDCD4, EGR1 and PTEN., In gastric cancer, PDCD4 plays a prominent tumor suppressor role. Previous studies indicated that PDCD4, as a significant tumor suppressor in gastric cancer, is one of the target genes of miR-183. PDCD4 expression in gastric cancer can be a promising prognosis indicator for the disease outcome. miR-183 can inhibit apoptosis in human gastric cells by repressing the PDCD4 expression. Functional studies has illustrated that miR-183-5p plays a potential oncogenic role in CRC progression and metastasis possibly by contributing to the downregulation of EGR1 and PTEN as two important tumor suppressor genes. Recent studies revealed that PTEN is a well-described negative regulator of the PI3K/Akt pathway, and the loss of PTEN expression in PI3K/Akt pathway may be central to sporadic colon carcinogenesis. Moreover, evaluating the effect of promoter methylation on the PTEN expression status in CRC tissues showed that the aberrant promoter methylation caused a downregulation of PTEN expression is significantly associated with tumor stage and tumor differentiation in CRC. On the other hand, miR-183 has been shown to inhibit tumor invasion and metastasis by blocking MAPK/ERK signaling and suppressing EZR expression in gastric, breast, lung cancers, and osteosarcoma.,,,
Furthermore, recent findings showed that the level of miR-183-5p expression is associated with LNM and pathological TNM stage. In consistent with our study recent research revealed that miR-183-5p expression in stage II CRC tissues is higher than that in adjacent normal tissues, and patients with higher miR-183-5p expression have more LNM. Another study on lung cancer showed that compared to adjacent non-cancerous lung tissues and normal volunteers, members of the miR-183 family were highly expressed in lung cancer primary tissues and sera. Furthermore, Abraham et al. reported that upregulation of miR-183 in tissue specimens of medullary thyroid cancer could be predicted LNM. We note that opposite results have also been reported. Specifically, a functional study was done by Wang et al. about the role of miR-183 in lung and breast cancer cells malignancy assumed that miR-183 was a potential metastasis inhibitor, and its overexpression could inhibit the migration of cancer cells. This study demonstrated that miR-183-induced dysregulation of genes associated with migration and invasion in lung cancer and breast cancer cells, especially Ezrin.
The current study had a few limitations related to small sample sizes as well as a lack of comparative analysis with malignancies other than CRC. Thus, future studies with a larger sample size will be needed to confirm the benefit of miR-183-5p analyzed in this study for the prediction of LNM in CRC.
| > Conclusion|| |
These new data on the functions of miR-183-5p in CRC suggest that further studies will be needed to clarify its functions in the various stages and histological subtypes in different types of CRC tumors. This would be significantly improve the accuracy of the prediction for LNM and new prognostic targets.
The authors would like to thank the Deputy of Research, Iran University of Medical Sciences, for financially supporting this study. We also thank the patients who participated in the study. All authors declare that they have no competing conflicts of interests.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]