Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 
ORIGINAL ARTICLE
Ahead of print publication  

Diagnostic potential of differentially regulated microRNAs among endometriosis, endometrioid ovarian cancer, and endometrial cancer


1 Department of Zoology, Panjab University, Chandigarh, India
2 Department of Obstetrics and Gynecology; Department of Cytology and Gynecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission11-Nov-2019
Date of Acceptance27-Jan-2020
Date of Web Publication22-Oct-2020

Correspondence Address:
Indu Sharma,
Department of Zoology, Panjab University, Chandigarh - 160 014
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_969_19

 > Abstract 


Background: There is an increased risk of developing endometrioid ovarian and endometrial cancer in patients with endometriosis and there are no definitive diagnostic biomarkers available for these three associated diseases. Therefore, we evaluated the diagnostic potential of differentially expressed microRNAs (miRNAs) from the tissue samples of endometriosis, endometrioid ovarian cancer, and endometrial cancer to establish them as biomarkers for these diseases.
Materials and Methods: Ten samples of each, i.e., endometriosis, endometrioid ovarian cancer, endometrial cancer and control healthy endometrium were enrolled after obtaining ethical clearance. Differential expression of miR-16, miR-20a, miR-99b, miR-125a, miR-143, and miR-145 and some of their target genes, i.e., vascular endothelial growth factor (VEGF), hypoxia inducible factor 1A (HIF1A), cyclooxygenase 2 (COX2), and tumor necrosis factor (TNF) were quantified using quantitative reverse transcription polymerase chain reaction. Receiver operating characteristic (ROC) curve analysis was performed to predict the diagnostic potential.
Results: miR-16 and miR-20a were significantly downregulated, whereas miR-99b, miR-125a, and miR-143 were significantly upregulated in all three diseased samples. miR-145 was significantly upregulated in endometriosis and endometrioid ovarian cancer but significantly downregulated in endometrial cancer. mRNA levels of VEGF, HIF1A, COX2, and TNF were significantly increased in all three diseased samples as compared to control samples. ROC curve analysis revealed that for endometriosis, miR-99b, and miR-125a were giving highest area under curve (AUC) (0.950 and 0.733, respectively), for endometrioid carcinoma of ovary miR-143 was giving highest AUC (0.933) and for endometrioid endometrial cancer miR-16 (AUC = 0.815), miR-99b (AUC = 0.920), and miR-145 (AUC = 0.985) were found to be best predictors.
Conclusion: These findings suggest that these miRNAs can act as good predictors and discriminators of these three diseases and might serve as potential biomarkers for them.

Keywords: Endometrioid endometrial cancer, endometrioid ovarian cancer, endometriosis, microRNA



How to cite this URL:
Kumari P, Sharma I, Saha SC, Srinivasan R, Minhas P. Diagnostic potential of differentially regulated microRNAs among endometriosis, endometrioid ovarian cancer, and endometrial cancer. J Can Res Ther [Epub ahead of print] [cited 2020 Dec 2]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=298869




 > Introduction Top


Endometriosis is a most frequent estrogen-dependent gynecological disease, in which ectopic endometrium develops outside the uterine cavity with an array of symptoms such as dysmenorrhea, dyspareunia, pelvic pain, and infertility.[1] Endometriosis shows similarity to malignancies in certain ways such as metastasizing tendency, escalating, invasive, and estrogen-dependent growth with chances of reappearance.[2] Exact mechanism and etio-pathology of endometriosis is still ambiguous.

Risk of developing ovarian cancer increases in women having endometriosis.[3] Around 15%–50% of clear-cell and endometrioid type of ovarian tumors were associated with endometriosis and there are two-to-three-fold risk of developing ovarian carcinoma in patients having endometriosis in their early age.[4],[5],[6] However, endometrioid ovarian cancers share many molecular features with endometrioid endometrial cancers as well;[7],[8],[9] therefore, it is plausible that endometriosis may also increase the risk of developing endometrial cancer at later age.

MicroRNAs (miRNAs) are small approximately 22–23 nucleotide long endogenous, noncoding RNAs which posttranscriptionally regulates gene expression through either inhibition of mRNA translation or less frequently degradation of mRNA.[10] Numerous recent studies showed that differential miRNA expression might be one of the important factors in the pathogenesis and progression of endometriosis as well as endometrioid subtypes of endometrial and ovarian carcinomas[11],[12],[13] and altered miRNA expression are involved in initiation, progression, and transformation of endometriosis as well as ovarian and endometrial cancer. There are several studies which states specific miRNAs may act as promising noninvasive biomarkers in the molecular diagnosis of these three diseases.[14],[15],[16]

From the previous published studies, we selected six miRNAs (miR-16, miR-20a, miR-99b, miR-125a, miR-143, and miR-145) which besides targeting the genes of interest also play key role in the pathogenesis of endometriosis, endometrioid ovarian cancer, and endometrioid endometrial cancer separately.[17],[18],[19],[20],[21],[22],[23],[24],[25] We hypothesized that these miRNAs would be involved in regulation of common processes such as hypoxia, inflammation, angiogenesis, and cell proliferation which are common in pathophysiology of endometriosis, endometrioid carcinoma of the ovary, and endometrioid endometrial cancer and may act as important diagnostic tools and potential link in associating these three diseases with other genetic as well as epigenetic factors. Therefore, in the present study, we compared the differential expression of these six miRNAs and some of the common target genes of these miRNAs and tried to find the diagnostic potential of these miRNAs in discriminating these three debilitating diseases.


 > Materials and Methods Top


Sample collection and ethical clearance

The present study was carried out from 2016 to 2019 for the period of 3 years. Ethical approval of the study has been obtained from the “Institutional Ethics Committee” of the Institutes. Histopathologically, confirmed cases (n = 40) were enrolled in the study of which Group I comprises; Group-Ia: Subjects with endometriosis (n = 10), Group-Ib: Subjects with endometrioid type of ovarian cancer (n = 7 [fresh] +3 Formalin-fixed paraffin-embedded [FFPE] tissues) Group-Ic: Subjects with endometrioid endometrial cancer (n = 10), and Group II comprises: Controls with healthy endometrium (n = 10), with no records of tumor complication.

After taking written informed consents from the patients, tissue samples were collected in vials containing RNA later at PGIMER Gynae Operation Theater at the time of laparoscopy/laparotomy/hysterectomy and stored at −80°C till further experiments. FFPE tissue blocks of endometrioid carcinoma of ovary (n = 3) were also obtained. Baseline characteristics and clinical data of all the study groups are shown in [Table 1].
Table 1: Baseline characteristics of patients included in the study

Click here to view


MicroRNAs rich RNA isolation and cDNA synthesis

miRNA rich RNA isolated from the tissue samples by using commercially available miRNeasy® Mini Kit (Cat # 217004, Qiagen India Pvt., Ltd., New Delhi, India) according to the manufacturer's instructions. From the FFPE tissue samples, RNA was extracted by using recover all total nucleic acid isolation kit for FFPE (Cat # AM1975, Invitrogen, USA) using manufacturer's instructions. Total 1 μg/μl of RNA (for fresh tissue) and 200 ng/μl RNA (for FFPE tissue) was reverse transcribed by miScript II RT Kit (Cat # 21816, Qiagen India Pvt., Ltd., New Delhi) for cDNA synthesis.

Quantitative reverse transcription-polymerase chain reaction to check microRNAs expressions and mRNA levels of target genes

The expression patterns of all selected miRNAs (miR-16, miR-20a, miR-99b, miR-125a, miR-143, and miR-145) were analyzed by real-time polymerase chain reaction (PCR) (Light Cycler LC96 Real-Time PCR system, Roche applied science, USA) by using miScript SYBR Green PCR Kit, (Cat # 218073, Qiagen, India Pvt., Ltd., New Delhi) with specific miRNA primer assays for each miRNA (miScript Primer assays, Qiagen, India Pvt., Ltd., New Delhi). U6 snRNA was used as an internal reference control. Furthermore, the expression pattern of some of the target genes of previously selected miRNAs promoting angiogenesis and inflammation, i.e., vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1A (HIF1A), cyclooxygenase 2 (COX2), and tumor necrosis factor (TNF) were quantified by using same method. Glyceraldehyde 3-phosphate dehydrogenase and β-actin housekeeping genes were used as reference controls. Melting curve and cycle threshold values were obtained, and the relative quantification of all miRNAs and target mRNA expression was determined by 2ΔΔCt method.[26] Primers used for individual miRNA/gene and their annealing temperature are summarized in [Table 2].
Table 2: Primers sequences of genes/MicroRNAs used in the study

Click here to view


Statistical analysis

Statistical software IBM SPSS Statistical Package 22.0 (IBM, Armonk, New York, US) was used to perform all the statistical analysis. Data were represented as mean ± standard deviation (SD) or SD from standard error of the mean as appropriate. Kolmogorov–Smirnov test was used to check the normality of the data. The expression levels of miRNAs and mRNA levels of their target genes between control group and three disease groups were compared using Kruskal–Wallis test and within groups by Mann–Whitney test as appropriate. To check the diagnostic potential of all differentially expressed miRNAs, receiver operating characteristic (ROC) curve analysis was performed on all miRNAs to investigate the diagnostic accuracy of these miRNAs in three diseases and also for each individual disease.


 > Results Top


Expression of miR-16, miR-20a, miR-99b, miR-125a, miR-143, and miR-145 in all study groups

We have observed statistically significant downregulated expression of miR-16 and miR-20 P=0.000 or P < 0.001 in endometriosis, endometrioid type of endometrial cancer, and ovarian cancer study participants as compared to controls. Expression of miR-99b, miR-125a, and miR-143 were found to be statistically upregulated in all three diseased study participants as compared to controls P=0.000 or P < 0.001 as shown in [Figure 1]. miR-145 was significantly upregulated in endometriosis and endometrioid carcinoma of the ovary P=0.000 or P < 0.001, but in endometrioid endometrial cancer, its levels were significantly downregulated P=0.000 or P < 0.001.
Figure 1: Expression levels of microRNAs in the tissue samples of endometriosis, endometrioid ovarian cancer and endometrioid endometrial cancer study participants as compared to controls. (a) miR-16, (b) miR-20a, (c) miR-99b, (d) miR-125a, (e) miR-143, and (f) miR-145. Note: Data are represented as box plots. Boxes represent the 25th and 75th percentile, with a solid line with in the box showing median value

Click here to view


Evaluation of target gene prediction for all selected microRNAs

Using miRWalk 3.0 and Target Scan online tools we have predict the target genes for selected miRNAs, i.e., miR-16, miR-20a, miR-99b, miR-125a, miR-143, and miR-145. Each micro RNA targets thousands of genes, but we mainly focus on the genes promoting angiogenesis and inflammation which are the main regulatory processes in the pathogenesis of endometriosis and endometrioid type of ovarian and endometrial cancer. miR-16 and miR-20a targets many genes operational in hypoxia such as HIF1A, inflammation (COX2 and TNF), and angiogenesis (VEGF). Whereas, miR-99b, miR-125a, miR-143, and miR-145 mainly targets the genes involved in cell proliferation, tumor suppression, and tissue remodeling pathways.

Relative mRNA levels of target genes of selected microRNAs in all study subjects

Results of the present study revealed that mRNA levels of VEGF, HIF1A, COX2, and TNF were statistically significantly increased in endometriosis, endometrioid carcinoma of the ovary and endometrioid endometrial cancer P=0.000 or P < 0.001 as compared to controls as shown in [Figure 2].
Figure 2: Expression levels of vascular endothelial growth factor A, hypoxia inducible factor 1A, cyclooxygenase 2, and tumor necrosis factor genes (a-d) in the tissue samples of endometriosis, endometrioid ovarian cancer, and endometrioid endometrial cancer study subjects as compared to controls. Note: Data are represented as box plots. Boxes represent the 25th and 75th percentile, with a solid line with in the box showing median value

Click here to view


Assessment of diagnostic potential of selected microRNAs using receiver operating characteristics curve analysis

To check the diagnostic potential of these six miRNAs expression for endometriosis, endometrioid ovarian, and endometrial cancer, ROC analysis was done [Figure 3].
Figure 3: Receiver operating characteristics curves of different microRNAs in endometriosis, endometrioid ovarian cancer, and endometrioid endometrial cancer. (a) For endometriosis miR-99b and miR-125a showed the highest area under curve of 0.950 and 0.733, respectively. (b) For endometrioid ovarian cancer, miR-143 gives the highest area under curve of 0.933. (c) For endometrioid endometrial cancer, miR-16, miR-99b, and miR-145 gives the highest area under curve values of 0.815, 0.920, and 0.985, respectively

Click here to view


For endometriosis disease, miR-99b and miR-125a showed the highest area under curve (AUC) 0.950 (95% confidence interval [CI], 0.857–1.000, P = 0.000), and 0.733 (95% CI, 0.551–0.914, P = 0.041), respectively. We have calculated sensitivity and specificity for miR-99b and miR-125a expression levels. miR-99b displayed sensitivity and specificity of 90% and 95%, respectively, at the cutoff value of 2.945 and miR-125a displayed sensitivity and specificity of 90% and 60%, respectively, at the cutoff value of 2.15 in discriminating endometriosis from endometrioid ovarian carcinoma and endometrioid endometrial cancer.

For endometrioid carcinoma of the ovary, miR-143 showed the highest AUC of 0.933 (95% CI, 0.842–1.000, P = 0.000). It displayed sensitivity and specificity of 90% and 80%, respectively, at the cutoff value of 3.89 in discriminating endometrioid carcinoma of the ovary from the other two diseases.

For endometrioid endometrial cancer, miR-16, miR-99b, and miR-145 gives the highest AUC values of 0.815 (95% CI, 0.620–1.000, P = 0.006), 0.920 (95% CI, 0.820–1.00, P = 0.000) and 0.985 (95% CI, 0.950–1.00, P = 0.000), respectively. Here, miR-16 displayed sensitivity and specificity of 80% and 90%, respectively, at the cut-off value of 0.255. Sensitivity and specificity for miR-99b were calculated 80% and 90%, respectively, at the cut-off value of 1.93 and for miR-145, sensitivity and specificity showed values 90% and 85%, at the cut-off value of 1.00 in discriminating endometrioid endometrial cancers from other two diseases. [Table 3], [Table 4], [Table 5] represent the AUC for miR-16, miR-20a, miR-99b, miR-125a, miR-143, and miR-145 expression levels in all three diseases.
Table 3: Area under curves for miR-16, miR-20a, miR-99b, miR-125a, miR-143, and miR-145 expression levels for endometriosis disease group

Click here to view
Table 4: Area under curves for miR-16, miR-20a, miR-99b, miR-125a, miR-143 and miR-145 expression levels for endometrioid ovarian cancer disease group

Click here to view
Table 5: Area under curves for miR-16, miR-20a, miR-99b, miR-125a, miR-143 and miR-145 expression levels for endometrioid endometrial cancer disease group

Click here to view



 > Discussion Top


In the present study, we evaluated the expression of miR-16, miR-20a, miR-99b, miR-125a, miR-143, and miR-145 in the tissue samples of endometriosis, endometrioid ovarian cancer, and endometrioid endometrial cancer along with the expression of inflammatory and angiogenesis promoting genes (VEGF, HIF1A, COX2, and TNF). We observed significant differential expression of miRNAs under consideration along with the significant upregulated expression of genes. Further, ROC curve analysis was also done to check the diagnostic potential of study miRNAs in differentiating these diseases for their early diagnosis and finding possible molecular mechanisms associating with these three diseases.

Since their discovery, miRNAs have been shown to play an important role in various physiological processes and their role in cancer development is also widely known. Several papers have been published on the possible role of miRNAs in pathogenesis endometriosis, endometrioid ovarian carcinoma, and endometrioid endometrial carcinoma,[27],[28],[29] but there is lack of much research in finding miRNAs which can actually discriminate these three diseases and helps in better diagnosis and deciding treatment strategies.

For the first time, the role of miRNAs differential regulation in human cancer development was shown in a type of leukemia (B-cell chronic lymphocytic leukemia), where miR-15/16 expression was downregulated.[30] Downregulation of miR-16 was also observed in the present study in endometriosis and endometrioid type of ovarian and endometrial cancers as compared to healthy controls. ROC curve analysis showed that miR-16 was a good predictor for endometrioid endometrial cancer with AUC of 0.815 (P = 0.006). It displayed a sensitivity and specificity of 80% and 90%, respectively, at the cutoff value of 0.255. We also predicted targets of miR-16 by miRwalk and Target scan online tools, and VEGF, HIF1A, and TNF genes were found to be targets of miR-16. Furthermore, the mRNA levels of these target genes were found to be upregulated in endometriosis, endometrioid ovarian cancer, and endometrioid endometrial cancer (P = 0.000). Thus, we can say that the downregulation of miR-16 might play an important role in inducing hypoxia, inflammation, and angiogenesis in these three diseases and miR-16 might act as good diagnostic biomarkers for endometrioid endometrial cancer.

In the present study, expression of miR-20a was found to be significantly decreased in endometriosis, endometrioid ovarian cancer, and endometrioid endometrial cancer (P = 0.000) as compared to control samples. Downregulation of miR-20a was previously confirmed by many studies in endometriosis.[19],[31],[32] We also predicted the targets of miR-20a by miRwalk and Target Scan online tools and HIF1A, TNF, and VEGF genes were found to be the targets of miR-20a. Furthermore, the mRNA levels of these target genes of miR-20a were significantly upregulated in endometriosis, endometrioid ovarian cancer, and endometrioid endometrial cancer as compared to controls. Thus, we can say that miR-20a downregulation might be the promoter of hypoxia, inflammation, and angiogenesis in these three diseases and plays an important role in the pathogenesis of these three debilitating diseases.

Further, in this study, miR-99b was found to be significantly upregulated in endometriosis as well as endometrioid ovarian and endometrial cancer study participants (P = 0.000) as compared to controls. According to studies of Ohlsson Teague et al., 2009, upregulated expression miR-99b was found in ectopic endometriotic tissue as compared to control healthy endometrium and surfaced as an important player in the pathogenesis of endometriosis by targeting angiogenic pathways.[19] miR-99b belongs to the miR-99 family, which consists of three members, miR-99a, miR-99b, and miR-100. Several studies have shown that the miR-99 family regulates cell survival, cell stress response, proliferation, angiogenesis, DNA damage, and wound healing process.[33],[34],[35],[36],[37],[38],[39] In the present study, ROC curve analysis revealed miR-99b as a good predictor for endometriosis showing AUC of 0.950 (95% CI, 0.857–1.000, P =0.000) and displayed sensitivity and specificity of 90% and 95% respectively, at the cut-off value of 2.945. Based on our observation and evidence from the literature, miR-99b seems to be important in the pathogenesis of endometriosis with good diagnostic potential in discriminating endometriosis from the rest of the two cancerous diseases. However, the role of overexpression of miR-99b in endometrioid carcinoma of the ovary and endometrioid endometrial cancer is still not fully understood and more research in this field would definitely help in better understanding of this miRNA family in the pathogenesis and progression of these two cancers.

In the previous studies, miR-125a was upregulated in endometriosis which would repress Erythroblastic leukemia viral oncogene homologue (ERBB) signaling as well as control cell migration and invasion.[19] In the present study, miR-125a was observed to be upregulated in endometriosis along with AUC of 0.733 (95% CI, 0.551–0.914, P = 0.041) and thus differentiate endometriosis from endometrioid carcinoma of the ovary and endometrioid endometrial cancer. We also observed upregulated expression of miR-125a in endometrioid subtypes of ovarian and endometrial cancer which are in contrast with some previous studies with downregulated expression in the same disease.[40],[41],[42] Since the endometrioid histological subtype of ovarian and endometrial cancer share many similarities with endometriosis; hence, miR-125a upregulation suggests some common molecular pathogenesis of these three diseases. However, more directed research is required to find out the exact role of miR-125a in the pathogenesis and progression of endometrioid subtype of ovarian and endometrial cancer.

Further, miR-143 and mir-145 belong to the miR143/miR145 cluster which usually coexpressed in many types of cancers.[43] In the present study, miR-143 was significantly upregulated in endometriosis, endometrioid ovarian carcinoma and endometrioid endometrial carcinoma (P = 0.000), but miR-145 was significantly upregulated in endometriosis and endometrioid carcinoma of the ovary (P = 0.000) and significantly downregulated in endometrioid endometrial cancer (P = 0.000). Both miR-143 and miR-145 were upregulated in endometriosis[19],[44] with a predicted role in suppression of cell proliferation by repressing growth-promoting proteins mitogen-activated protein kinase 7[45] and Kirsten rat sarcoma viral oncogene homologue (KRAS),[46] thereby, helps in cell survival of endometriotic cells. In endometriosis, increased expression of miR-145 may regulate several important processes such as the growth of the endometriotic lesion, invasiveness, and long-term establishment of the lesion by downregulation of its target genes such as JAM-A, PAI-1 etc.[47] Thus, we conclude that miR-143 and 145 might play a significant role in the pathogenesis and progression of endometriosis.

In addition, ROC curve analysis revealed miR-143 as a good predictor of endometrioid carcinoma of ovary with AUC of 0.933 (P = 0.000, 95% CI, 0.842–1.000) and displayed sensitivity and specificity of 90% and 80%, respectively, at the cutoff value of 3.89 in discriminating endometrioid ovarian cancer, from endometriosis and endometrioid endometrial cancer. Zhang et al. concluded that, upregulated expression of miR-143 results posttranscriptional suppression of its target gene (fibronectin type III domain-containing 3B) and results in enhanced cell invasion and migration.[48] Corroborating to this, we can also speculate aberrant miR-143 as an imperial player in progression and pathogenesis of endometrioid type of ovarian cancer and may act as an important noninvasive biomarker for this particular disease. Future studies in this direction would be helpful in finding the possible role of miR-143 in the pathogenesis of these three associated diseases.

ROC curve analysis revealed that miR-145 is a good predictor for endometrioid endometrial cancer with AUC of 0.985 (95% CI, 0.950–1.000, P = 0.000) in discriminating endometrioid endometrial cancer from rest of two diseases. Downregulation of miR-145 has been reported in endometrial cancer with possible role in enhanced expression of its target genes such as SOX11 which is tumorigenic in nature.[49] Hence, current findings enhance the possibility of the pivotal role of miR-145 in the pathogenesis and progression of endometrial cancer and its potential use as a biomarker for this specific disease.

However, the validation of target genes of these differentially expressed miRNAs is necessary to estimate the role of these miRNAs in posttranscriptional regulation of hypoxia, angiogenesis, and inflammation in endometriosis and endometrioid subtypes of ovarian and endometrial cancer. The sample size of the present study was also small to give concluding statements but future studies on the large population will further reveal the role of these miRNAs as diagnostic and therapeutic targets. Although thousands of miRNAs are involved in the complex pathogenesis of endometriosis, endometrioid ovarian and endometrial cancer, definitely there might be some common molecular denominators that may associate these three complex disorders. It seems very necessary to accurately diagnose them in deciding treatment strategies.


 > Conclusion Top


In summary, we can conclude that, studied miRNAs can act as potential biomarkers for early detection and discrimination of these three ambiguous diseases. Observations of present study pointed significant operational leads, which can be further targeted and help in deciding accurate biomarkers for these three debilitating diseases in age specific manner. More importantly, a precise strategy should be set up for better prevention, early detection, specific diagnosis, and treatment targeting molecular pathogenesis to understand the mechanism of endometriosis and associated cancer subtypes.

Financial support and sponsorship

DST-SERB (ECR/2016/000359), UGC JRF (22/06/2014(i) EU-V) New Delhi, India and UGC CAS-II (F.4-28/2015 [CAS-II] [SAP-II]) New Delhi, India.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Rogers PA, D'Hooghe TM, Fazleabas A, Gargett CE, Giudice LC, Montgomery GW, et al. Priorities for endometriosis research: Recommendations from an international consensus workshop. Reprod Sci 2009;16:335-46.  Back to cited text no. 1
    
2.
Flores I, Rivera E, Ruiz LA, Santiago OI, Vernon MW, Appleyard CB. Molecular profiling of experimental endometriosis identified gene expression patterns in common with human disease. Fertil Steril 2007;87:1180-99.  Back to cited text no. 2
    
3.
Aris A. Endometriosis-associated ovarian cancer: A ten-year cohort study of women living in the Estrie Region of Quebec, Canada. J Ovarian Res 2010;3:2.  Back to cited text no. 3
    
4.
Brinton LA, Sakoda LC, Sherman ME, Frederiksen K, Kjaer SK, Graubard BI, et al. Relationship of benign gynecologic diseases to subsequent risk of ovarian and uterine tumors. Cancer Epidemiol Biomarkers Prev 2005;14:2929-35.  Back to cited text no. 4
    
5.
Rossing MA, Cushing-Haugen KL, Wicklund KG, Doherty JA, Weiss NS. Risk of epithelial ovarian cancer in relation to benign ovarian conditions and ovarian surgery. Cancer Causes Control 2008;19:1357-64.  Back to cited text no. 5
    
6.
Forte A, Cipollaro M, Galderisi U. Genetic, epigenetic and stem cell alterations in endometriosis: New insights and potential therapeutic perspectives. Clin Sci (Lond) 2014;126:123-38.  Back to cited text no. 6
    
7.
Kurman RJ, Shih IM. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer – Shifting the paradigm. Hum Pathol 2011;42:918-31.  Back to cited text no. 7
    
8.
McConechy MK, Anglesio MS, Kalloger SE, Yang W, Senz J, Chow C, et al. Subtype-specific mutation of PPP2R1A in endometrial and ovarian carcinomas. J Pathol 2011;223:567-73.  Back to cited text no. 8
    
9.
McConechy MK, Ding J, Senz J, Yang W, Melnyk N, Tone AA, et al. Ovarian and endometrial endometrioid carcinomas have distinct CTNNB1 and PTEN mutation profiles. Mod Pathol 2014;27:128-34.  Back to cited text no. 9
    
10.
Bartel DP. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 2004;116:281-97.  Back to cited text no. 10
    
11.
Bao W, Wang HH, Tian FJ, He XY, Qiu MT, Wang JY, et al. A TrkB-STAT3-miR-204-5p regulatory circuitry controls proliferation and invasion of endometrial carcinoma cells. Mol Cancer 2013;12:155.  Back to cited text no. 11
    
12.
Braicu OL, Budisan L, Buiga R, Jurj A, Achimas-Cadariu P, Pop LA, et al. miRNA expression profiling in formalin-fixed paraffin-embedded endometriosis and ovarian cancer samples. Onco Targets Ther 2017;10:4225-38.  Back to cited text no. 12
    
13.
Ma J, Li D, Kong FF, Yang D, Yang H, Ma XX. miR-302a-5p/367-3p-HMGA2 axis regulates malignant processes during endometrial cancer development. J Exp Clin Cancer Res 2018;37:19.  Back to cited text no. 13
    
14.
Suryawanshi S, Vlad AM, Lin HM, Mantia-Smaldone G, Laskey R, Lee M, et al. Plasma microRNAs as novel biomarkers for endometriosis and endometriosis-associated ovarian cancer. Clin Cancer Res 2013;19:1213-24.  Back to cited text no. 14
    
15.
Wilczynski M, Danielska J, Dzieniecka M, Szymanska B, Wojciechowski M, Malinowski A. Prognostic and clinical significance of miRNA-205 in endometrioid endometrial cancer. PLoS One 2016;11:e0164687.  Back to cited text no. 15
    
16.
Liu Y, Chen J, Zhu X, Tang L, Luo X, Shi Y. Role of miR-449b-3p in endometriosis via effects on endometrial stromal cell proliferation and angiogenesis. Mol Med Rep 2018;18:3359-65.5.  Back to cited text no. 16
    
17.
Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, et al. MicroRNA signatures in human ovarian cancer. Cancer Res 2007;67:8699-707.  Back to cited text no. 17
    
18.
Nam EJ, Yoon H, Kim SW, Kim H, Kim YT, Kim JH, et al. MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res 2008;14:2690-5.  Back to cited text no. 18
    
19.
Ohlsson Teague EM, Van der Hoek KH, Van der Hoek MB, Perry N, Wagaarachchi P, Robertson SA, et al. MicroRNA-regulated pathways associated with endometriosis. Mol Endocrinol 2009;23:265-75.  Back to cited text no. 19
    
20.
Resnick KE, Hampel H, Fishel R, Cohn DE. Current and emerging trends in Lynch syndrome identification in women with endometrial cancer. Gynecol Oncol 2009;114:128-34.  Back to cited text no. 20
    
21.
Wyman SK, Parkin RK, Mitchell PS, Fritz BR, O'Briant K, Godwin AK, et al. Repertoire of microRNAs in epithelial ovarian cancer as determined by next generation sequencing of small RNA cDNA libraries. PLoS One 2009;4:e5311.  Back to cited text no. 21
    
22.
Zhang J, Sun Q, Zhang Z, Ge S, Han ZG, Chen WT. Loss of microRNA-143/145 disturbs cellular growth and apoptosis of human epithelial cancers by impairing the MDM2-p53 feedback loop. Oncogene 2013;32:61-9.  Back to cited text no. 22
    
23.
Xiong H, Li Q, Liu S, Wang F, Xiong Z, Chen J, et al. Integrated microRNA and mRNA transcriptome sequencing reveals the potential roles of miRNAs in stage I endometrioid endometrial carcinoma. PLoS One 2014;9:e110163.  Back to cited text no. 23
    
24.
Schwarzenbach H. Clinical significance of miR-15 and miR-16 in ovarian cancer. Transl Cancer Res 2016;5:S50-3.  Back to cited text no. 24
    
25.
Zheng B, Xue X, Zhao Y, Chen J, Xu CY, Duan P. The differential expression of microRNA-143,145 in endometriosis. Iran J Reprod Med 2014;12:555-60.  Back to cited text no. 25
    
26.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001;25:402-8.  Back to cited text no. 26
    
27.
Dahiya N, Morin PJ. MicroRNAs in ovarian carcinomas. Endocr Relat Cancer 2010;17:F77-89.  Back to cited text no. 27
    
28.
Wu RL, Ali S, Bandyopadhyay S, Alosh B, Hayek K, Daaboul MF, et al. Comparative analysis of differentially expressed miRNAs and their downstream mRNAs in ovarian cancer and its associated endometriosis. J Cancer Sci Ther 2015;7:258-65.  Back to cited text no. 28
    
29.
Delangle R, De Foucher T, Larsen AK, Sabbah M, Azaïs H, Bendifallah S, et al. The use of microRNAs in the management of endometrial cancer: A meta-analysis. Cancers (Basel) 2019;11. pii: E832.  Back to cited text no. 29
    
30.
Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 2002;99:15524-9.  Back to cited text no. 30
    
31.
Jia SZ, Yang Y, Lang J, Sun P, Leng J. Plasma miR-17-5p, miR-20a and miR-22 are down-regulated in women with endometriosis. Hum Reprod 2013;28:322-30.  Back to cited text no. 31
    
32.
Wang L, Huang W, Ren C, Zhao M, Jiang X, Fang X, et al. Analysis of serum microRNA Profile by solexa sequencing in women with endometriosis. Reprod Sci 2016;23:1359-70.  Back to cited text no. 32
    
33.
Zhang H, Luo XQ, Zhang P, Huang LB, Zheng YS, Wu J, et al. MicroRNA patterns associated with clinical prognostic parameters and CNS relapse prediction in pediatric acute leukemia. PLoS One 2009;4:e7826.  Back to cited text no. 33
    
34.
Doghman M, El Wakil A, Cardinaud B, Thomas E, Wang J, Zhao W, et al. Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors. Cancer Res 2010;70:4666-75.  Back to cited text no. 34
    
35.
Sun D, Lee YS, Malhotra A, Kim HK, Matecic M, Evans C, et al. miR-99 family of MicroRNAs suppresses the expression of prostate-specific antigen and prostate cancer cell proliferation. Cancer Res 2011;71:1313-24.  Back to cited text no. 35
    
36.
Chen Z, Jin Y, Yu D, Wang A, Mahjabeen I, Wang C, et al. Down-regulation of the microRNA-99 family members in head and neck squamous cell carcinoma. Oral Oncol 2012;48:686-91.  Back to cited text no. 36
    
37.
Zheng YS, Zhang H, Zhang XJ, Feng DD, Luo XQ, Zeng CW, et al. MiR-100 regulates cell differentiation and survival by targeting RBSP3, a phosphatase-like tumor suppressor in acute myeloid leukemia. Oncogene 2012;31:80-92.  Back to cited text no. 37
    
38.
Jin Y, Tymen SD, Chen D, Fang ZJ, Zhao Y, Dragas D, et al. MicroRNA-99 family targets AKT/mTOR signaling pathway in dermal wound healing. PLoS One 2013;8:e64434.  Back to cited text no. 38
    
39.
Mueller AC, Sun D, Dutta A. The miR-99 family regulates the DNA damage response through its target SNF2H. Oncogene 2013;32:1164-72.  Back to cited text no. 39
    
40.
Jayaraman M, Radhakrishnan R, Mathews CA, Yan M, Husain S, Moxley KM, et al. Identification of novel diagnostic and prognostic miRNA signatures in endometrial cancer. Genes Cancer 2017;8:566-76.  Back to cited text no. 40
    
41.
Yang HP, Murphy KR, Pfeiffer RM, George N, Garcia-Closas M, Lissowska J, et al. Lifetime number of ovulatory cycles and risks of ovarian and endometrial cancer among postmenopausal women. Am J Epidemiol 2016;183:800-14.  Back to cited text no. 41
    
42.
Lee M, Kim EJ, Jeon MJ. MicroRNAs 125a and 125b inhibit ovarian cancer cells through post-transcriptional inactivation of EIF4EBP1. Oncotarget 2016;7:8726-42.  Back to cited text no. 42
    
43.
Akao Y, Nakagawa Y, Naoe T. MicroRNAs 143 and 145 are possible common onco-microRNAs in human cancers. Oncol Rep 2006;16:845-50.  Back to cited text no. 43
    
44.
Cosar E, Mamillapalli R, Ersoy GS, Cho S, Seifer B, Taylor HS. Serum microRNAs as diagnostic markers of endometriosis: A comprehensive array-based analysis. Fertil Steril 2016;106:402-9.  Back to cited text no. 44
    
45.
Akao Y, Nakagawa Y, Naoe T. MicroRNA-143 and -145 in colon cancer. DNA Cell Biol 2007;26:311-20.  Back to cited text no. 45
    
46.
Chen X, Guo X, Zhang H, Xiang Y, Chen J, Yin Y, et al. Role of miR-143 targeting KRAS in colorectal tumorigenesis. Oncogene 2009;28:1385-92.  Back to cited text no. 46
    
47.
Adammek M, Greve B, Kässens N, Schneider C, Brüggemann K, Schüring AN, et al. MicroRNA miR-145 inhibits proliferation, invasiveness, and stem cell phenotype of anin vitro endometriosis model by targeting multiple cytoskeletal elements and pluripotency factors. Fertil Steril 2013;99:1346-55.  Back to cited text no. 47
    
48.
Zhang ZQ, Meng H, Wang N, Liang LN, Liu LN, Lu SM, et al. Serum microRNA 143 and microRNA 215 as potential biomarkers for the diagnosis of chronic hepatitis and hepatocellular carcinoma. Diagn Pathol 2014;9:135.  Back to cited text no. 48
    
49.
Chang YS, Huang HD, Yeh KT, Chang JG. Identification of novel mutations in endometrial cancer patients by whole-exome sequencing. Int J Oncol 2017;50:1778-84.  Back to cited text no. 49
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

 
Top
 
 
  Search
 
     Search Pubmed for
 
    -  Kumari P
    -  Sharma I
    -  Saha SC
    -  Srinivasan R
    -  Minhas P
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  >Abstract>Introduction>Materials and Me...>Results>Discussion>Conclusion>Article Figures>Article Tables
  In this article
>References

 Article Access Statistics
    Viewed71    
    PDF Downloaded3    

Recommend this journal