Research ArticleClinical studies

miR-7 Expression in Serous Ovarian Carcinomas

ANETA SWIERCZ, MAGDALENA CHECHLINSKA, JOLANTA KUPRYJANCZYK, AGNIESZKA DANSONKA-MIESZKOWSKA, ALINA REMBISZEWSKA, KRZYSZTOF GORYCA, MARIUSZ KULINCZAK, MICHALINA ZAJDEL, MARIA SROMEK and JAN KONRAD SIWICKI
Anticancer Research April 2015, 35 (4) 2423-2429;

Abstract

Background/Aim: miR-7 has recently been linked to cancer. Some miR-7 targets, including B-cell lymphoma 2 (BCL2) and epidermal growth factor receptor (EGFR), are involved in ovarian cancer (OC) pathogenesis. The majority of OCs display TP53 mutations, which are critically important for OC development. We aimed to study the expression level of miR-7 and of two of its postulated target genes, BCL2 and EGFR, in serous ovarian carcinomas of different TP53 status and tumour grade. Materials and Methods: Gene and miR expression was assessed by real-time reverse transcription polymerase chain reaction in 45 clinical samples of low- (G1+G2) and high- (G3) grade primary serous OC with wild-type (wt) or mutated TP53, as well as in three OC cell lines, each representing a different TP53 status. The results obtained in patients with OC were analysed against their disease-free survival (DFS). Results: In high-grade OC with TP53 mutations, the level of miR-7 expression significantly exceeded (by several fold) that in wtTP53 cancer (p<0.01). Within the wtTP53 tumour series, the level of miR-7 expression was significantly higher (by over 10-fold) in high-grade than in low-grade OC (p<0.01). miR-7 expression was not found to influence DFS. The differences in miR-7 expression depending on TP53 status found in clinical OC samples were not observed in OC cell lines. miR-7 overexpression correlated with diminished BCL2 expression, but there was no relationship between miR-7 and EGFR expression, neither in tumour samples nor in the cell lines. Conclusion: There is a link between miR-7 expression and TP53 status and tumour grade in serous OC. Molecular mechanisms of these relationships need to be elucidated. Of the two postulated miR-7 target genes we examined, BCL2, but not EGFR, seems to be a possible miR-7 target in OC.

Over the past decade, microRNAs (miRs) have emerged as important components of carcinogenesis (1). In this context, miR-7 attracted attention only recently. Depending on cancer type and experimental model, it has been suggested that miR-7 plays the role of a tumour suppressor or of an oncogene (2-7). However, decreased miR-7 expression has frequently been observed, and functional studies point to a tumour-suppressor role of miR-7. In ovarian cancer, scarce and inconsistent data are available. Shahab et al. showed miR-7 overexpression in ovarian cancer specimens (8), while other researchers observed no alterations in miR-7 expression in ovarian cancer (9-11).

The potential role of miR-7 in carcinogenesis is further supported by the links of the predicted miR-7 targets to cell-to-cell interaction, adhesion, polarity of epithelial cells, proliferation, apoptosis and survival (3, 6, 12-15). Several postulated miR-7 target genes are known to play important roles in oncogenesis, B-cell lymphoma 2 (BCL2) and epidermal growth factor receptor (EGFR) genes among them (7). BCL2 is an inhibitor of apoptosis, and it has been proposed that it has diagnostic, prognostic and predictive value in ovarian cancer (16). EGFR is a cell membrane receptor, which activates mitogen-activated protein kinase, serine-threonine protein kinase and c-Jun N-terminal kinase pathways, crucial to DNA synthesis and cell proliferation. EGFR overexpression in advanced ovarian cancer leads to increased proliferation and impairment of apoptosis, and it correlates with poor prognosis (17).

TP53 is the most frequently mutated gene in different malignancies. In ovarian carcinomas TP53 mutations have a predictive value (18). The highest frequency of TP53 mutations in ovarian cancer is observed in undifferentiated carcinomas, followed by serous, mucinous and endometrioid (19-21). To our knowledge, the relationship between miR-7 expression and TP53 has not been studied either in ovarian or in any other type of cancer.

View this table:
Table I.

Serous ovarian cancer sample/patient characteristics according to TP53 mutation status and tumour grade.

We aimed to study the expression levels of miR-7 and of two of its postulated target genes, BCL2 and EGFR, in serous ovarian carcinomas characterised by different TP53 status and tumour grade. We analysed ovarian cancer specimens of serous type only, in order to reduce biological heterogeneity related to tumour type. The expression of miR-7, BCL2 and EGFR was also assessed in established ovarian cancer cell lines matching the clinical material in terms of TP53 status.

Materials and Methods

Clinical specimens and cell lines. Specimens of primary serous ovarian cancer taken during surgery from previously untreated patients were immediately snap-frozen and kept at −70°C in a biobank of the Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology in Warsaw. All patients gave their informed consent for the specimens to be submitted to the biobank. Adjacent microtome sections of frozen samples were taken for tumour histopathological 0characteristics based on standard methods, and for the assessment of cancer cell content, TP53 mutations, and microRNA and gene expression. The specimens included in the study were carefully selected from a larger collection so as to select those with at least 75% cancer cell content (the majority that have been included contained over 90% cancer cells), and to obtain series of samples characterised by different tumour grade and TP53 gene status [wild type (wt) TP53 vs. mutated TP53, with the assessed missense vs. null mutations]. TP53 mutational status was determined by polymerase chain reaction-single-strand conformation polymorphism and Sanger sequencing analysis of exons 4-11 of the TP53 gene (20). Forty-five samples included in the study fell into four categories, low-grade (G1 and G2) with wtTP53, high-grade (G3) with wtTP53, G3 with missense TP53 mutation, and G3 with null TP53 mutation. Patients were followed-up for 467 to 3926 days (median=1226 days), in order to assess disease-free survival (DFS). Patient and sample characteristics are summarised in Table I.

Figure 1.
Figure 1.

Relative miR-7 expression in clinical samples of primary serous ovarian cancer with different TP53 status and tumour grade (G). The expression of miR-7 transcript in normal human ovarian surface epithelial cells was set as the reference level (=1).

Three ovarian cancer cell lines derived from ovarian carcinomas with different TP53 status, A2780 (wtTP53; purchased from the European Collection of Cell Cultures, Porton Down, Salisbury, UK), TOV112D (missense TP53 mutation; ATCC® CRL-11731™), and SK-OV-3 (null TP53 mutation; ATCC® HTB77™), in three biological replicates each, were examined for the expression of miR-7, BCL2 and EGFR.

Expression quantification. Total RNA was extracted from frozen tissues and cell lines using mirVana miRNA Isolation Kit (Applied Biosystems, Life Technologies Ltd., Warrington, UK), according to the manufacturer's instructions. The quantity and quality of the RNA samples were analysed using a NanoDrop-1000 spectrophotometer (Thermo Fisher Scientific Inc., Waltham, MA USA). RNA integrity was checked in a 2100 Bioanalyzer (Agilent Technologies, Santa Clara, CA, USA), and/or by electrophoresis in a denaturating 1.5% agarose gel. The expression of miR-7 and genes (TP53, BCL2, EGFR) was quantified by reverse transcription real-time polymerase chain reaction with the use of TaqMan MicroRNA Assays, TaqMan Gene Expression Assays, TaqMan® MicroRNA Reverse Transcription Kit, High-Capacity cDNA Reverse Transcription Kits (Applied Biosystems), following the manufacturer's instructions. Based on the NormFinder algorithm (22) results, small nucleolar RNAs, RNU6B and RNU48, were chosen as reference points for microRNA expression, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and phosphoglycerate kinase (PGK) for gene expression assessment. Relative expression was calculated using the comparative -ΔΔCt method, against the calibrator level.

Figure 2.
Figure 2.

Relative expression of miR-7 (a), B-cell lymphoma 2 (BCL2) (b) and epidermal growth factor receptor (EGFR) (c) in ovarian cancer cell lines with different TP53 mutation status. The expression of the respective transcript in normal human ovarian surface epithelial cells was set as the reference level (=1).

Choosing the appropriate reference tissue for ovarian cancer studies is a challenge. Firstly, the pathogenesis of ovarian cancer is not clear. Ovarian surface epithelium has long been widely regarded as the source of serous ovarian cancer, but very recent evidence strongly suggests the fallopian tube epithelium to be the site of origin [reviewed in: (23)]. Nevertheless, it has been suggested that the two epithelium types are parts of a transitional epithelium of common origin rather than two independent sources of ovarian cancer (24). Secondly, obtaining a sufficient quantity of fresh, reference epithelial cells is difficult. Thus, in ovarian cancer studies, specimens of a normal whole ovary are often used as reference samples (9,10), which, by definition contain different cell types. Viral oncogene- or telomerase-immortalised cells of normal ovarian epithelium or normal ovarian epithelial cells following a short in vitro culture provide an alternative, single-cell-type reference material (8, 25, 26). Considering the above, we used normal human ovarian surface epithelium cells (HOSEpiC, cat. no.7310; Scien Cell Res. Lab. Carlsbad, CA, USA) following a short in vitro culture (HOSE) as a calibrator.

Statistical analyses. The Mann-Whitney U-test was used to examine the differences in microRNA and gene expression. Relationships between miR-7 and gene expression were assessed according to Spearman correlation coefficients. The Cox proportional hazard model was used to assess the relation between miR-7 expression levels and DFS. The significance threshold was set at 0.05.

Results

miR-7 expression in tumour samples of primary serous ovarian cancer. miR-7 expression in high-grade ovarian cancer samples significantly related to the presence vs. absence of TP53 mutations (p<0.01), and in wtTP53 ovarian cancer samples to tumour grade (p<0.01) (Figure 1). There was no correlation between miR-7 and TP53 expression at the transcript level.

In high-grade ovarian cancer with TP53 mutation, miR-7 expression did not differ depending on the TP53 mutation type (missense vs. null).

miR-7 expression was found not to influence the probability of DFS (data not shown).

miR-7 expression in ovarian cancer cell lines. The pattern of miR-7 expression in the context of the TP53 status in ovarian cell lines differed from that in clinical material. Namely, miR-7 expression level was the highest in A2780 ovarian cancer cells, characterised by wtTP53. TOV112D ovarian cancer cells, bearing missense TP53 mutation, exhibited lower miR-7 expression than A2780 cells, and SK-OV-3 ovarian cancer cells, characterised by a null mutation of TP53, had the lowest level of miR-7 expression (Figure 2a). BCL2. In clinical samples, the level of BCL2 expression did not relate to TP53 mutation status or tumour grade (Figure 3). There was a moderate inverse correlation (R=−0.31; p<0.05) between the levels of BCL2 and miR-7 transcripts. A2780 and SK-OV-3 ovarian cancer cell lines (Figure 2b) expressed several fold higher levels of BCL2 transcript than did the TOV112D cell line.

Figure 3.
Figure 3.

Relative B-cell lymphoma 2 (BCL2) transcript levels in clinical samples of primary serous ovarian cancer with different TP53 status and tumour grade (G). The expression of BCL2 transcript in normal human ovarian surface epithelial cells was set as the reference level (=1).

EGFR. There were no differences in EGFR transcript levels depending on TP53 status or tumour grade (Figure 4). The levels of EGFR transcript were found not to correlate with miR-7 levels. Notably lower levels of EGFR mRNA were expressed in A2780 and TOV112D ovarian cell lines than in the SK-OV-3 cell line (Figure 2c).

Discussion

To our knowledge, this is the first study on miR-7 expression in serous ovarian carcinomas. We show that in clinical specimens of high-grade serous ovarian cancer, miR-7 expression relates to the mutation status of the TP53 gene, with significantly higher miR-7 levels accompanying TP53 mutations, but does not depend on the mutation type (missense vs. null). In wtTP53 tumours, miR-7 expression significantly related to tumour grade, with higher levels in high-grade tumours. The results suggest that miR-7 expression increases with tumour malignancy. The levels of miR-7 did not influence the DFS of patients.

The interplay between miR-7 and TP53 needs to be examined in functional studies, but lower miR-7 levels observed in wtTP53 cancer raises the possibility that miR-7 expression is negatively regulated by the TP53 pathway. However, the lack of correlation between miR-7 and TP53 at the transcript level implies a possible involvement of components of the TP53 pathway other than TP53 itself in this relationship.

Figure 4.
Figure 4.

Relative epidermal growth factor receptor (EGFR) transcript levels in clinical samples of primary serous ovarian cancer with different TP53 status and tumour grade (G). The expression of EGFR transcript in normal human ovarian surface epithelial cells was set as the reference level (=1).

The relationship between miR-7 expression and TP53 status was not reflected in the cell lines. This and other discrepancies between the results obtained in ovarian cancer tissue and the cell lines support the notion that the molecular context of cell lines may be far removed from that of the relevant tumours, which points to the importance of studying clinical specimens, and has serious implications for the relevance of some functional studies considering TP53 status in ovarian cancer cell lines.

The available data linking miR-7 and TP53 status are scarce. Four ovarian cancer cell lines examined by Creighton et al., including one cell line with wtTP53 (HEY) and one with mutated TP53 (SK-OV-3, in which the published miR-7 expression was comparable to our results for this cell line), expressed diverse levels of miR-7, inconsistent with regard to the TP53 status (27). Veerla et al. reported that all urothelial G1 and G2 cancer confined to the urothelial mucosa had wtTP53, and presented distinctively low levels of miR-7 (28). Recently, it was demonstrated in colorectal cancer that the mechanism of the tumour-inhibitory role of miR-7 lies in a direct suppression of oncogenic YY1, a negative regulator of TP53 and of its downstream effectors, which include p15, caspase and JUN proto-oncogene (29). If this is true in ovarian cancer, low miR-7 expression in wtTP53 compared to TP53-mutated cancer might result in inactivation or attenuation of the TP53 pathway. A tumour-suppressor role of miR-7 has been shown in lung, breast and hepatocellular carcinomas and gliomas by ectopic miR-7 expression which resulted in suppression of cell growth and viability, apoptosis induction, migration inhibition, and reduced tumourigenicity. However, most of these cancer types have been shown to exhibit decreased miR-7 expression (4, 6, 7, 13-15, 29-31). Higher expression of miR-7 in TP53-mutated and high-grade ovarian tumours does not contradict a possible tumour-suppressor role of miR-7, and may reflect a secondary, context-dependent phenomenon, as discussed in other aggressive types of cancer (32, 33).

In line with our results, Shahab et al. have recently found higher miR-7 expression in advanced serous ovarian cancer vs. HOSE (8). Wyman et al. found a significantly higher miR-7 expression in serous vs. clear cell ovarian carcinomas (11). Two other studies that profiled miRs in ovarian cancer did not show miR-7 to be differentially expressed between tumour and normal ovarian tissue (9, 10). Contrary to our results, Iorio et al. found no miRs to be associated with tumour grade (9). These discrepancies may result from differences in the reference tissues and fold change (FC) thresholds applied, and in the different histopathological subtypes examined. Nam et al. (10) and Iorio et al. (9) used whole ovary, not HOSE, as a reference tissue. We examined a series of serous carcinomas, but others studied ovarian carcinomas of different histopathological types. Furthermore, we, as well as Shahab et al. (8) and Nam et al. (10), analysed data at a threshold FC of >2, while Wyman et al. (11) and Iorio et al. (9) did so at FC>4 and >3, respectively. In accordance with our results, in patients with breast cancer, the levels of miR-7 positively correlated with tumour grade (33).

The miR-7–BCL2 relationship has only been shown in a lung cancer cell line (7). Here we found a moderate negative correlation between miR-7 and BCL2 expression in ovarian cancer samples. A possible relationship between miR-7 and BCL2 expression was also supported by our results in ovarian cancer cell lines. Our results suggest that miR-7 targets BCL2 in ovarian carcinoma. EGFR has been validated as the target gene of miR-7 in a few studies, including studies on ovarian cancer (4, 6). In our series of ovarian cancer specimens, the expression of miR-7 was found not to correlate with EGFR expression, just as in studies on breast carcinoma (34). The lack of correlation between miR-7 and one of its postulated targets exemplifies the phenomenon of an incoherent expression of microRNAs and their presumed targets. Shahab et al. studying serous ovarian cancer specimens showed that the expression of only approximately 10% of miR-7 putative targets inversely correlated with miR-7 expression, and approximately 5% correlated positively, while in miR-7-transfected ovarian cancer cell line, these proportions ranged from approximately 8 to 23% (inverse correlation) and from 0 to approximately 1% (positive correlation), depending on the software used for target predictions (8). They obtained similar results for other miRNAs. In addition, on average, only 4% of miR-7 targets that were significantly down-regulated after ectopic expres sion of miR-7 in the HEY ovarian cancer cell line presented changes in expression that negatively correlated with miR-7 expression in ovarian tumour specimens (8). Nevertheless, the same studies described EGFR but not BCL2 as being down-regulated in miR-7-transfected HEY cells. Furthermore, in ovarian cancer specimens, Shahab et al. described EGFR to correlate negatively with miR-7 expression, but only one out of four EGFR Affymetrix probes was down-regulated in tumour tissues, while two out of three BCL2 probes were down-regulated and one was up-regulated (8). Incoherence between the expression of miRs and their postulated targets may also relate to tissue specificity of the miR-to-target relationship. Furthermore, many gene expres sion changes may be secondary, because on one hand transfection of a single miR can change the expression of thousands of genes, and on the other, fewer than 20% of the genes affected following miR transfection are the predicted targets, as shown for miR-7 in HEY ovarian cancer cells (8, 35).

In summary, in high-grade serous ovarian cancer, the level of miR-7 expression is significantly increased in TP53-mutated tumours, while in wtTP53 tumours, miR-7 expression significantly rises with increasing tumour grade. miR-7 in primary serous ovarian cancer emerges as a correlate of TP53 mutation status and grade. Correlation analyses point to BCL2 but not to EGFR as a possible target of miR-7 in ovarian cancer. Functional studies are necessary to elucidate molecular mechanisms linking miR-7 to TP53 status and tumour grade in ovarian cancer.

Acknowledgements

The Authors would like to thank Anna Leonowicz for her excellent technical assistance. This work was supported by the Polish Ministry of Science and Higher Education grant no. NN 401 050138.

Footnotes

  • ↵* These Authors contributed equally to this study.

  • Received December 1, 2014.
  • Revision received January 15, 2015.
  • Accepted January 19, 2015.

References

  1. ↵
    1. Lu J,
    2. Getz G,
    3. Miska EA,
    4. Alvarez-Saavedra E,
    5. Lamb J,
    6. Peck D,
    7. Sweet-Cordero A,
    8. Ebert BL,
    9. Mak RH,
    10. Ferrando AA,
    11. Downing JR,
    12. Jacks T,
    13. Horvitz HR,
    14. Golub TR
    : MicroRNA expression profiles classify human cancers. Nature 435: 834-838, 2005.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Chou YT,
    2. Lin HH,
    3. Lien YC,
    4. Wang YH,
    5. Hong CF,
    6. Kao YR,
    7. Lin SC,
    8. Chang YC,
    9. Lin SY,
    10. Chen SJ,
    11. Chen HC,
    12. Yeh SD,
    13. Wu CW
    : EGFR promotes lung tumorigenesis by activating miR-7 through a RAS/ERK/MYC pathway that targets the ETS2 transcriptional repressor ERF. Cancer Res 70: 8822-8831, 2010.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Jiang L,
    2. Liu X,
    3. Chen Z,
    4. Jin Y,
    5. Heidbreder CE,
    6. Kolokythas A,
    7. Wang A,
    8. Dai Y,
    9. Zhou X
    : MicroRNA-7 targets IGF1R (insulin-like growth factor 1 receptor) in tongue squamous cell carcinoma cells. Biochem J 432: 199-205, 2010.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Kefas B,
    2. Godlewski J,
    3. Comeau L,
    4. Li Y,
    5. Abounader R,
    6. Hawkinson M,
    7. Lee J,
    8. Fine H,
    9. Chiocca EA,
    10. Lawler S,
    11. Purow B
    : MicroRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma. Cancer Res 68: 3566-3572, 2008.
    OpenUrlAbstract/FREE Full Text
    1. Skalsky RL,
    2. Cullen BR
    : Reduced expression of brain-enriched microRNAs in glioblastomas permits targeted regulation of a cell death gene. PLoS One 6: e24248, 2011.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Webster RJ,
    2. Giles KM,
    3. Price KJ,
    4. Zhang PM,
    5. Mattick JS,
    6. Leedman PJ
    : Regulation of epidermal growth factor receptor signaling in human cancer cells by microRNA-7. J Biol Chem 284: 5731-5741, 2009.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Xiong S,
    2. Zheng Y,
    3. Jiang P,
    4. Liu R,
    5. Liu X,
    6. Chu Y
    : MicroRNA-7 inhibits the growth of human non-small cell lung cancer A549 cells through targeting BCL2. Int J Biol Sci 7: 805-814, 2011.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Shahab SW,
    2. Matyunina LV,
    3. Mezencev R,
    4. Walker LD,
    5. Bowen NJ,
    6. Benigno BB,
    7. McDonald JF
    : Evidence for the complexity of microRNA-mediated regulation in ovarian cancer: a systems approach. PLoS One 6: e22508, 2011.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Iorio MV,
    2. Visone R,
    3. Di Leva G,
    4. Donati V,
    5. Petrocca F,
    6. Casalini P,
    7. Taccioli C,
    8. Volinia S,
    9. Liu CG,
    10. Alder H,
    11. Calin GA,
    12. Menard S,
    13. Croce CM
    : MicroRNA signatures in human ovarian cancer. Cancer Res 67: 8699-8707, 2007.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Nam EJ,
    2. Yoon H,
    3. Kim SW,
    4. Kim H,
    5. Kim YT,
    6. Kim JH,
    7. Kim JW,
    8. Kim S
    : MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res 14: 2690-2695, 2008.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Wyman SK,
    2. Parkin RK,
    3. Mitchell PS,
    4. Fritz BR,
    5. O'Briant K,
    6. Godwin AK,
    7. Urban N,
    8. Drescher CW,
    9. Knudsen BS,
    10. Tewari M
    : Repertoire of microRNAs in epithelial ovarian cancer as determined by next-generation sequencing of small RNA cDNA libraries. PLoS One 4: e5311, 2009.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Nguyen HT,
    2. Dalmasso G,
    3. Yan Y,
    4. Laroui H,
    5. Dahan S,
    6. Mayer L,
    7. Sitaraman SV,
    8. Merlin D
    : MicroRNA-7 modulates CD98 expression during intestinal epithelial cell differentiation. J Biol Chem 285: 1479-1489, 2010.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Xu L,
    2. Wen Z,
    3. Zhou Y,
    4. Liu Z,
    5. Li Q,
    6. Fei G,
    7. Luo J,
    8. Ren T
    : MicroRNA-7-regulated TLR9 signaling-enhanced growth and metastatic potential of human lung cancer cells by altering the phosphoinositide-3-kinase, regulatory subunit 3/AKT pathway. Mol Biol Cell 24: 42-55, 2013.
    OpenUrlAbstract/FREE Full Text
    1. Reddy SD,
    2. Ohshiro K,
    3. Rayala SK,
    4. Kumar R
    : MicroRNA-7, a homeobox D10 target, inhibits p21-activated kinase 1 and regulates its functions. Cancer Res 68: 8195-8200, 2008.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Saydam O,
    2. Senol O,
    3. Wurdinger T,
    4. Mizrak A,
    5. Ozdener GB,
    6. Stemmer-Rachamimov AO,
    7. Yi M,
    8. Stephens RM,
    9. Krichevsky AM,
    10. Saydam N,
    11. Brenner GJ,
    12. Breakefield XO
    : miRNA-7 attenuation in Schwannoma tumors stimulates growth by up-regulating three oncogenic signaling pathways. Cancer Res 71: 852-861, 2011.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Ziolkowska-Seta I,
    2. Madry R,
    3. Kraszewska E,
    4. Szymanska T,
    5. Timorek A,
    6. Rembiszewska A,
    7. Kupryjanczyk J
    : TP53, BCL-2 and BAX analysis in 199 ovarian cancer patients treated with taxane-platinum regimens. Gynecol Oncol 112: 179-184, 2009.
    OpenUrlCrossRefPubMed
  17. ↵
    1. Bull Phelps SL,
    2. Schorge JO,
    3. Peyton MJ,
    4. Shigematsu H,
    5. Xiang LL,
    6. Miller DS,
    7. Lea JS
    : Implications of EGFR inhibition in ovarian cancer cell proliferation. Gynecol Oncol 109: 411-417, 2008.
    OpenUrlCrossRefPubMed
  18. ↵
    1. Kupryjanczyk J,
    2. Kraszewska E,
    3. Ziolkowska-Seta I,
    4. Madry R,
    5. Timorek A,
    6. Markowska J,
    7. Stelmachow J,
    8. Bidzinski M
    : TP53 status and taxane-platinum versus platinum-based therapy in ovarian cancer patients: a non-randomized retrospective study. BMC Cancer 8: 27, 2008.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Bardos AP
    1. Kupryjanczyk J
    : TP53 Status Determines Prognostic and Predictive Factors in Ovarian Carcinomas. In: Trends in Ovarian Cancer Research. Bardos AP (ed.). New York: Nova Science Publishers, Inc., pp. 93-111, 2004.
  20. ↵
    1. Dansonka-Mieszkowska A,
    2. Ludwig AH,
    3. Kraszewska E,
    4. Kupryjanczyk J
    : Geographical variations in TP53 mutational spectrum in ovarian carcinomas. Ann Hum Genet 70: 594-604, 2006.
    OpenUrlCrossRefPubMed
  21. ↵
    Integrated genomic analyses of ovarian carcinoma. Nature 474: 609-615, 2011.
    OpenUrlCrossRefPubMed
  22. ↵
    1. Andersen C.L,
    2. Ledet-Jensen J,
    3. Ørntoft T
    : Normalization of real-time quantitative RT-PCR data: a model based variance estimation approach to identify genes suited for normalization - applied to bladder- and colon-cancer data-sets. Cancer Res 64: 5245-5250, 2004.
    OpenUrlAbstract/FREE Full Text
  23. ↵
    1. Dubeau L,
    2. Drapkin R
    : Coming into focus: the nonovarian origins of ovarian cancer. Ann Oncol 24 (Suppl 8): viii28-viii35, 2013.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    1. Auersperg N
    : The origin of ovarian carcinomas: a unifying hypothesis. Int J Gynecol Pathol 30: 12-21, 2011.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Dahiya N,
    2. Sherman-Baust CA,
    3. Wang TL,
    4. Davidson B,
    5. Shih Ie M,
    6. Zhang Y,
    7. Wood W 3rd.,
    8. Becker KG,
    9. Morin PJ
    : MicroRNA expression and identification of putative miRNA targets in ovarian cancer. PLoS One 3: e2436, 2008.
    OpenUrlCrossRefPubMed
  26. ↵
    1. Zhang L,
    2. Volinia S,
    3. Bonome T,
    4. Calin GA,
    5. Greshock J,
    6. Yang N,
    7. Liu CG,
    8. Giannakakis A,
    9. Alexiou P,
    10. Hasegawa K,
    11. Johnstone CN,
    12. Megraw MS,
    13. Adams S,
    14. Lassus H,
    15. Huang J,
    16. Kaur S,
    17. Liang S,
    18. Sethupathy P,
    19. Leminen A,
    20. Simossis VA,
    21. Sandaltzopoulos R,
    22. Naomoto Y,
    23. Katsaros D,
    24. Gimotty PA,
    25. DeMichele A,
    26. Huang Q,
    27. Butzow R,
    28. Rustgi AK,
    29. Weber BL,
    30. Birrer MJ,
    31. Hatzigeorgiou AG,
    32. Croce CM,
    33. Coukos G
    : Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer. Proc Natl Acad Sci USA 105: 7004-7009, 2008.
    OpenUrlAbstract/FREE Full Text
  27. ↵
    1. Creighton CJ,
    2. Fountain MD,
    3. Yu Z,
    4. Nagaraja AK,
    5. Zhu H,
    6. Khan M,
    7. Olokpa E,
    8. Zariff A,
    9. Gunaratne PH,
    10. Matzuk MM,
    11. Anderson ML
    : Molecular profiling uncovers a p53-associated role for microRNA-31 in inhibiting the proliferation of serous ovarian carcinomas and other cancers. Cancer Res 70: 1906-1915, 2010.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Veerla S,
    2. Lindgren D,
    3. Kvist A,
    4. Frigyesi A,
    5. Staaf J,
    6. Persson H,
    7. Liedberg F,
    8. Chebil G,
    9. Gudjonsson S,
    10. Borg A,
    11. Mansson W,
    12. Rovira C,
    13. Hoglund M
    : miRNA expression in urothelial carcinomas: important roles of miR-10a, miR-222, miR-125b, miR-7 and miR-452 for tumor stage and metastasis, and frequent homozygous losses of miR-31. Int J Cancer 124: 2236-2242, 2009.
    OpenUrlCrossRefPubMed
  29. ↵
    1. Zhang N,
    2. Li X,
    3. Wu CW,
    4. Dong Y,
    5. Cai M,
    6. Mok MT,
    7. Wang H,
    8. Chen J,
    9. Ng SS,
    10. Chen M,
    11. Sung JJ,
    12. Yu J
    : MicroRNA-7 is a novel inhibitor of YY1 contributing to colorectal tumorigenesis. Oncogene 32: 5078-5088, 2013.
    OpenUrlCrossRefPubMed
    1. Fang Y,
    2. Xue JL,
    3. Shen Q,
    4. Chen J,
    5. Tian L
    : MicroRNA-7 inhibits tumor growth and metastasis by targeting the phosphoinositide 3-kinase/AKT pathway in hepatocellular carcinoma. Hepatology 55: 1852-1862, 2012.
    OpenUrlCrossRefPubMed
  31. ↵
    1. Kong X,
    2. Li G,
    3. Yuan Y,
    4. He Y,
    5. Wu X,
    6. Zhang W,
    7. Wu Z,
    8. Chen T,
    9. Wu W,
    10. Lobie PE,
    11. Zhu T
    : MicroRNA-7 inhibits epithelial-to-mesenchymal transition and metastasis of breast cancer cells via targeting FAK expression. PLoS One 7: e41523, 2012.
    OpenUrlCrossRefPubMed
  32. ↵
    1. Jung HM,
    2. Phillips BL,
    3. Patel RS,
    4. Cohen DM,
    5. Jakymiw A,
    6. Kong WW,
    7. Cheng JQ,
    8. Chan EK
    : Keratinization-associated miR-7 and miR-21 regulate tumor suppressor reversion-inducing cysteine-rich protein with kazal motifs (RECK) in oral cancer. J Biol Chem 287: 29261-29272, 2012.
    OpenUrlAbstract/FREE Full Text
  33. ↵
    1. Foekens JA,
    2. Sieuwerts AM,
    3. Smid M,
    4. Look MP,
    5. de Weerd V,
    6. Boersma AW,
    7. Klijn JG,
    8. Wiemer EA,
    9. Martens JW
    : Four miRNAs associated with aggressiveness of lymph node-negative, estrogen receptor-positive human breast cancer. Proc Natl Acad Sci USA 105: 13021-13026, 2008.
    OpenUrlAbstract/FREE Full Text
  34. ↵
    1. Masuda M,
    2. Miki Y,
    3. Hata S,
    4. Takagi K,
    5. Sakurai M,
    6. Ono K,
    7. Suzuki K,
    8. Yang Y,
    9. Abe E,
    10. Hirakawa H,
    11. Ishida T,
    12. Suzuki T,
    13. Ohuchi N,
    14. Sasano H
    : An induction of microRNA, miR-7 through estrogen treatment in breast carcinoma. J Transl Med 10 Suppl 1: S2, 2012.
    OpenUrlPubMed
  35. ↵
    1. Shahab SW,
    2. Matyunina LV,
    3. Hill CG,
    4. Wang L,
    5. Mezencev R,
    6. Walker LD,
    7. McDonald JF
    : The effects of microRNA transfections on global patterns of gene expression in ovarian cancer cells are functionally coordinated. BMC Med Genomics 5: 33, 2012.
    OpenUrlCrossRefPubMed
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miR-7 Expression in Serous Ovarian Carcinomas
ANETA SWIERCZ, MAGDALENA CHECHLINSKA, JOLANTA KUPRYJANCZYK, AGNIESZKA DANSONKA-MIESZKOWSKA, ALINA REMBISZEWSKA, KRZYSZTOF GORYCA, MARIUSZ KULINCZAK, MICHALINA ZAJDEL, MARIA SROMEK, JAN KONRAD SIWICKI
Anticancer Research Apr 2015, 35 (4) 2423-2429;
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