The Role of MicroRNAs in Ovarian Cancer
Expression levels of top dysregulated miRNA genes, miR and miR-9, profiles between primary and recurrent serous papillary ovarian. We assessed the microRNA expression profiles which contribute to recurrence in advanced serous ovarian carcinoma. Methods: Eight pairs of. To assess the miRNA expression profiles in serous ovarian cancer, we and the majority of serous carcinomas are at an advanced stage at .. Correlation of miRNA expression with clinicopathological . Laios A, O'Toole S, Flavin R, et al: Potential role of miR-9 and miR in recurrent ovarian cancer.
A better understanding of molecular alterations in ovarian carcinoma is necessary to identify novel targets for early detection and improved treatment. They regulate target gene expression either by mRNA degradation or by translation repression [ 4 - 11 ].
Each miRNA may regulate up to hundreds of target genes [ 11 ]. During tumor development, aberrant expression of miRNAs can either inactivate tumor suppressor genes or activate oncogenes, thus promoting tumor formation [ 4 - 68 - 1012 ].
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Because expression of miRNAs is tissue-specific, detectable in blood [ 13 ], and correlates with clinical cancer behaviors [ 14 ], miRNAs are potential valuable biomarkers. Numerous studies have identified both upregulated and downregulated miRNAs in ovarian carcinoma samples, using both candidate gene [ 61315 ] and global profiling [ 16 - 25 ] approaches.
Aberrant expression of miRNAs has also been associated with tumor histology [ 619 ], response to therapy [ 2124 ] and survival [ 26 ].MicroRNAs and their regulatory effects
However, most studies have compared miRNA expression to either normal ovarian tissues or human ovarian surface epithelial HOSE cell lines; it is unknown whether these samples represent miRNA expression in normal ovarian epithelial cells [ 1827 ].
Using the TargetScan database http: In the present study, we determined the expression of these nine miRNAs in benign, borderline and ovarian carcinoma tissues, as well as HOSE cell lines and normal ovarian tissues by quantitative real-time reverse transcription-PCR.
Methods Clinical ovarian tissue samples A total of archived formalin-fixed, paraffin-embedded FFPE tissue blocks of normal ovaries 22and benign 17borderline 23 or ovarian carcinoma were obtained from the pathology department of Bucheon St. Histologic diagnoses were reviewed by two independent pathologists.
Normal and benign tissues were obtained from patients who had oophorectomy for benign uterine pathologies. Among these, the recently discovered microRNAs miRNAs or miRs constitute a novel layer of gene expression regulation and have been implicated in the etiology of ovarian cancer.
This review summarizes the ways in which microRNAs are involved in the pathogenesis of ovarian cancer and discusses cumulative efforts to apply them to the creation of novel diagnostic tools or promising future therapies.
Currently, it is well known that miRs can be upregulated or downregulated in various human cancers. Overexpressed miRs may function as oncogenes by downregulating tumor suppressor genes, whereas the downregulated miRs may act as tumor suppressor genes by negatively regulating oncogenes [ 9 ].
Important insights into the functions of miRs in cancer have been provided through the demonstration that they are involved in known oncogenic pathways.
Interestingly, the miRs of the let-7 family, which are typically downregulated in various tumors, have been shown to negatively regulate the RAS oncogenes, thereby acting as tumor suppressors [ 1011 ]. MiR and miR have been shown to target the BCL2 oncogene, leading to its downregulation and, consequently, resulting in apoptosis in leukemic cells [ 12 ].
MiR and miR are examples of miRs that act as oncogenes. They do so by targeting and inhibiting the expression of the tumor suppressor gene, p27Kip [ 13 ]. High levels of these miRs were shown to result in low p27 protein expression and increased proliferation of cancer cells. There is also evidence of a role of miR in pinduced cell death.
It has been shown that p53 transcriptionally induces miR expression, and this induction is important in pmediated apoptosis of cancer cells [ 71415 ]. These studies only represent a fraction of the explosion of publications emphasizing the role of miRs in cancer biology and showing miR dysregulation in various malignancies, including ovarian cancer. InMerritt et al. Low Dicer expression is significantly associated with advanced stage ovarian cancer and low Drosha expression with suboptimal surgery.
Low Dicer expression is an independent predictor of disease-specific survival in multivariate analysis, as well as high-grade histological finding and chemotherapy resistance. These results suggested that impaired processing of miRs by Dicer and Drosha is involved in the tumorigenesis of ovarian cancer and leads to poor clinical outcomes. In their study, higher Ago2 protein expression in ovarian cancer before chemotherapy correlated with shorter progression free survival.
The study group saw similar trends for both Ago1 and Ago2 with respect to overall survival, suggesting a pivotal role of these molecules in ovarian cancer progression.
Collectively, these reports demonstrate that enzymes and proteins involved in miR biogenesis and processing are closely related to development and progression in ovarian cancer. Numerous miRs are markedly downregulated in advanced stages or high-grade ovarian cancer, suggesting that miRs are involved in malignant transformation and tumor progression.
Both genomic copy number loss and epigenetic alteration may account for this downregulation and contribute to genome-wide transcriptional dysregulation.
MicroRNA expression in ovarian carcinoma and its correlation with clinicopathological features
The authors compared the miR expression profiles of 18 epithelial ovarian cancer EOC cell lines and 4 immortalized ovarian surface epithelium IOSE primary cultures. Of these, 31 miRs Of 29 miRs, they showed that only 4 miR, miRa, miRb, and miRc were upregulated and 25 were downregulated, including miRa, miR, miR, and miRb-1 in the cancer samples [ 21 ]. They also found that miR signatures were different between ovarian carcinoma histotypes serous, endometrioid, clear cell, and mucinous.
The clear cell histotype is characterized by higher expression of miRa-5p and miRa-3p, whereas mucinous histotype displays higher levels of miR and miR [ 22 ]. Thus, these reports identified similar sets of dysregulated miRs. Seventeen miRs showed differential expression in omental lesions compared to primary tumors. Among these, miRa and miR were significantly increased in omental metastases, regulating enhancement of spheroid formation and cisplatin resistance. They also showed that ovarian cancers could be separated into 4 transcriptional subtypes, 3 miR subtypes, and 4 promoter methylation subtypes.
Integrated genomic analysis revealed a miRNA-regulatory network that defined a robust integrated mesenchymal subtype associated with poor survival in cases of serous ovarian cancer and cases independent of cohort data [ 26 ]. Recently, Davidson et al. In addition, various miRs have also been identified as potential prognostic indicators and promise utility in future practice.
Characterization of microRNA expression in serous ovarian carcinoma
These are summarized in Table 1 [ 28 — 40 ]. Potential prognostic miRs for ovarian cancer, which are significant in multivariate analysis modified from [ 27 ]. Emerging evidence shows that miRs exist not only in cells but also in circulating blood, reflecting tissue or organ conditions. Circulatory miRs in blood are resistant to the degradation of RNase enzyme and remain stable [ 4243 ].
In addition, high miR expression was associated with relapse-free survival. The potential of circulating miRs as cancer biomarkers depends on their high stability and their capacity to reflect tumor status and predict therapy response [ 43 ].
Many studies have determined that circulating miRs remain stable after being subjected to harsh conditions that would normally degrade RNAs, such as boiling, extreme pH levels, extended storage time, and repetitive freeze-thaw cycles. This incredible stability is partly explained by the association of the miRs with protein complexes such as Ago2 and the presence of these small RNAs in circulating microvesicles such as exosomes.
Other proteins may also be associated with circulating miRs. Taylor and Gercel-Taylor reported that the miR signatures of tumor-derived exosomes have the potential to be used as diagnostic biomarkers of ovarian cancer [ 47 ]. Exosomes are small 30— nm lipoprotein vesicles that exist in body fluids. They contain proteins, mRNAs, and miRs and are thought to play important roles in intercellular communication. The researchers compared the expression profiles of 8 miRs miR, miR, miRa, miRb, miRc, miR, miR, and miR between cancer tissues and exosomes collected from the peripheral sera of the corresponding patients, since these had been previously demonstrated to be overexpressed in ovarian cancer.
Differential MicroRNA Expression Profiles in Primary and Recurrent Epithelial Ovarian Cancer
They showed that exosomal miR profiles from ovarian cancer patients were elevated, whereas the exosomal miRs could not be detected in normal healthy controls. MiR, miRa, miR, miR, and miR were significantly overexpressed in the serum of ovarian cancer patients compared to controls, while miRb, miR, and miR were significantly underexpressed.
A comparison between ovarian cancer patients and healthy controls detected significantly dysregulated miRs. In particular, miRcp was significantly upregulated and miRa-3p, miRp, and miRb-5p were significantly downregulated in ovarian cancer patients. They suggested that these signatures might serve as useful diagnostic markers for the discrimination of these diseases, which is often clinically difficult. These efforts strongly support the idea that the detection of ovarian cancer-associated miRs from the peripheral blood could become a valuable method for early diagnosis of this disease in future clinical practice.
Improving the sensitivity and lowering the cost of such detection methods are both key goals for advancing the application of detecting serum miR in cancer patients. Potential diagnostic miRs for ovarian cancer. Therapeutic Potential of miRs That Inhibit Ovarian Cancer Progression With the progress in cancer profiling, treatments will soon be customized for each individual.
Because each miR regulates the expression of hundreds of different genes, miRs can function as master coordinators, efficiently regulating and coordinating multiple cellular pathways and processes [ 5 ].
Thus, miRs have been suggested as possible therapeutic armaments against cancer. The therapeutic application of miRs involves two strategies, inhibiting oncogenic miRs by using miRNA antagonists and replacement of tumor suppressor miRs to restore a loss-of-function [ 54 ]. The miR family plays a critical role in the suppression of epithelial-to-mesenchymal transition EMT and tumor cell migration, invasion, and metastasis by directly targeting ZEB1 zinc finger E-box-binding homeobox 1 and ZEB2 [ 5556 ].
Both miR and miRa target p38 and modulate the oxidative stress response, affecting tumorigenesis and chemosensitivity [ 55 ]. They showed the therapeutic potential of miR delivery in treating ovarian cancer or other malignancies [ 58 ].
Furthermore, it has been reported that miR family members are associated with chemosensitivity in ovarian cancer. The restoration of miRc increased sensitivity to microtubule-binding chemotherapeutic drugs, paclitaxel, epothilone B, and vincristine and suppressed the expression of TUBB3. Van Jaarsveld et al. These miRs are located in cancer-associated regions or in fragile sites [ 68 ].