miR-93 and PTEN: Key regulators of doxorubicin-resistance and EMT in breast cancer

  • Authors:
    • Shihua Chu
    • Geng Liu
    • Peixuan Xia
    • Guoqing Chen
    • Feng Shi
    • Tao Yi
    • Hongying Zhou
  • View Affiliations

  • Published online on: July 31, 2017     https://doi.org/10.3892/or.2017.5859
  • Pages: 2401-2407
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

It is not well established whether miR-93 is involved in drug resistance and epithelial-mesenchymal transition (EMT) in breast cancer, and its underlying mechanism remains uncertain. In the present study, the expression differences of miR-93 between paired breast cancer tissues confirmed it is involved in the progression of breast cancer. Such a difference was also observed in doxorubicin-resistant and -sensitive cells. Overexpressed miR-93 in sensitive cells revealed increases in cellular proliferation and the expression levels of drug-resistant-related genes, and a decrease in sensitivity to doxorubicin. This demonstrated the relationship between miR-93 and breast cancer drug resistance. Simultaneously, EMT was confirmed in miR-93 overexpressing sensitive cells. This indicated the triadic relationship among miR-93, EMT and drug resistance in breast cancer. We applied the Dual-luciferase Reporter assay to expose the direct interaction between miR-93 and PTEN, which suggested that miR-93 contributes to inducing EMT and drug resistance of breast cancer cells by targeting PTEN.

Introduction

Breast cancer is the leading cause of cancer-related mortality among women (1). This high incidence of mortality is, to a large extent, due to drug-resistance, which is the major obstacle to successful clinical treatment (2).

Numerous studies have demonstrated that microRNAs (miRNAs) are involved in the process of epithelial-mesenchymal transition (EMT) in various types of cancer (36), and various studies have revealed that the EMT may be associated with the drug resistance of cancer cells (710). Furthermore, by comparing the miRNA expression profiles between breast cancer cell lines in our previous study, we determined that the expression of miR-93 was increased markedly in drug-resistant MCF-7/AdrVp cells compared with the parental MCF-7 cell line (11).

Numerous studies on breast cancer have demonstrated that PTEN is involved in EMT (5,12) and in the drug resistance of cancer cells (6,13). Although a few studies have shown that miR-93 may functionally interact with PTEN, this has only been reported in cardiomyocyte apoptosis, osteosarcoma, ovarian cancer, glioma, hepatocellular carcinoma and prostate cancer (1420). Therefore, it remains to be determined whether miR-93 is also functionally associated with PTEN in breast cancer, and whether such an association contributes to the induction of EMT and drug resistance in breast cancer cells. The present study aimed to clarify the role of miR-93 in drug resistance and EMT in breast cancer, and to investigate its target gene.

Materials and methods

Tissue samples

Sixteen pairs of tissue samples of ductal breast cancer were obtained from the West China Hospital of Sichuan University. All the patients underwent surgical resection to obtain the breast cancerous and corresponding adjacent non-tumorous tissues, without receiving chemotherapy or radiotherapy beforehand. All tissues were preserved in liquid nitrogen. The present study was approved by the local ethical standards of the Institutional Review Board of Sichuan University. Informed consent was obtained from all individual participants included in the present study.

Ethical approval

All procedures performed in the present study involving human participants were in accordance with the ethical standards of the Institutional and/or National Research Committee of Sichuan University and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Cell lines and transfections

The MCF-7 cell line was purchased from the Shanghai Institutes for Biological Sciences (Shanghai, China) and cultured according to a protocol from the ATCC.

The doxorubicin-resistant MCF-7/ADR cell line (MCF-7/ADR) was induced by continuously culturing MCF-7 cells in medium containing progressive concentrations of doxorubicin (Sigma-Aldrich, St. Louis, MO, USA). MCF-7/ADR cells were cultured in medium with 2 µg/ml doxorubicin, and subsequently transferred into a drug-free medium for at least 2–3 weeks before use in the assays.

Using Lipofectamine 3000 (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's instructions, MCF-7 cells were transfected with 50 nM hsa-miR-93-5p mimics or hsa-miR-93-5p negative control mimics (RiboBio Co., Ltd., Guangzhou, China) in order to produce an MCF-7-miR-93 mimics group (MCF-7-miR-93 mimics) and a negative control group (MCF-7-miR-93 mimics NC), respectively. In addition, MCF-7/ADR cells were transfected with 100 nM hsa-miR-93-5p inhibitor (RiboBio Co., Ltd.) to produce an MCF-7/ADR-miR-93 inhibitor group, or an hsa-miR-93-5p inhibitor negative control (RiboBio Co., Ltd.) to produce an MCF-7/ADR-miR-93 inhibitor NC group, following the same procedure as aforementioned.

RNA isolation and qRT-PCR

Total miRNAs were extracted from cells and tissue samples using an miRcute miRNA Isolation kit (Tiangen Biotech Co., Ltd., Beijing, China). The expression of miR-93 was analyzed using the Bulge-Loop™ miRNA qRT-PCR Starter kit (RiboBio Co., Ltd.). The primers for miR-93 and endogenous control U6 were purchased from RiboBio Co., Ltd. (ssD809230675, ssD809231367, ssD809261711, ssDD0904071006, ssDD0904071007 and ssDD0904071008).

TRIzol reagent (Takara, Dalian, China) was used for total RNA extraction. The expression of different genes was analyzed using a SYBR-Green qRT-PCR kit (Takara). The primer sequences for qRT-PCR were as follows: E-cadherin, 5′-tgcccagaaaatgaaaaagg-3′, 5′-gtgtatgtggcaatgcgttc-3′ (product size, 200 bp); vimentin, 5′-gagaactttgccgttgaagc-3, 5′-tccagcagcttcctgtaggt-3′ (product size, 170 bp); N-cadherin, 5′-gac aatgcccctcaagtgtt-3′, 5′-ccattaagccgagtgatggt-3′ (product size, 179 bp); fibronectin, 5′-accaacctacggatgactcg-3′, 5′-gctcatcatc tggccatttt-3′ (product size, 230 bp); Snail, 5′-ggttcttctgcgctactgct-3′, 5′-tagggctgctggaaggtaaa-3′ (product size, 157 bp); Twist, 5′-ggagtccgcagtcttacgag-3′, 5′-tggaggacctggtagaggaa-3′ (product size, 199 bp); MRP, 5′-aggtggacctgtttcgtgac-3′, 5′-cctg tgatccaccagaaggt-3′ (product size, 181 bp); BCRP, 5′-caccttattg gcctcaggaa-3′, 5′-cctgcttggaaggctctatg-3′ (product size, 206 bp); MDR, 5′-gctcctgactatgccaaagc-3′, 5′-tcttcacctccaggctcagt-3′ (product size, 202 bp); PTEN, 5′-ttacagttgggccctgtacc-3′, 5′-atttgatgctgccggtaaac-3′ (product size, 153 bp); GAPDH, 5′-ct ttggtatcgtggaaggactc-3′, 5′-gtagaggcagggatgatgttct-3′ (product size, 132 bp).

Flow cytometry

Cell apoptosis was detected using an Annexin V-FITC apoptosis detection kit (KeyGen Biotech Co., Ltd., Nanjing, China), according to the manufacturer's instructions. The data were analyzed using FlowJo 9.1 software.

CCK-8 assay

Cellular proliferation and growth inhibition were assessed using Cell Counting Kit-8 (CCK-8) assay (Dojindo Laboratories, Kumamoto, Japan) according to the manufacturer's protocol. For the detection of the proliferation of cells in the MCF-7-miR-93 mimic group, the cells were assessed at 0, 24, 48 and 72 h. In addition, to determine the effect of miR-93 on drug resistance, the cell survival ratio was assessed after cells in the MCF-7-miR-93 mimic group were cultured with 0.08, 0.4, 1 and 5 µg/ml doxorubicin (Sigma-Aldrich) for 24 h.

Dual-luciferase reporter assay

A bioinformatics analysis using the ‘miRanda’ database was performed to analyze the possibility of miR-93 binding to PTEN. Subsequently, MCF-7 cells were cotransfected with 2.5 µg pGL3 luciferase reporter plasmid (GeneCopoeia) containing either a wild-type (5′-GGAUUAAUAAAGAUGGCACUUUC-3′) or mutated (5′-GGAUUAAUAAAGAUGGCTCUAUC-3′) form of the PTEN 3′-UTR, and 50 nM hsa-miR-93-5p or miR-93 mimics NC in 6-well plates using Lipofectamine 3000. Luciferase activity was assessed consecutively at 24 h post-transfection using a Dual-Luciferase Assay (GeneCopoeia), and normalized to the blank vector control group.

Statistical analysis

All the experiments were repeated three times independently. Data were calculated as the mean ± SD. The paired t-test was applied for statistical analysis using SPSS software (version 20.0) (SPSS, Inc., Chicago, IL, USA).

Results

Expression of miR-93 in breast cancer in vivo and in vitro

qRT-PCR was performed to identify the patterns of miR-93 expression in breast cancer tissues and a doxorubicin-resistant breast cancer cell line (MCF-7/ADR) compared with paired normal breast tissue samples and a doxorubicin-sensitive parental breast cancer cell line (MCF-7). The results revealed that 62.5% of cancer tissue samples (10 out of 16 cases) exhibited a markedly higher expression level of miR-93 compared with their corresponding paired adjacent normal tissue (Fig. 1A; p<0.05). Furthermore, the miR-93 expression level in the MCF-7/ADR cells was significantly higher than that in MCF-7 cells (Fig. 1B; p<0.01).

Proliferation and doxorubicin-resistance of MCF-7 cells transfected with miR-93 mimics

A CCK-8 assay was performed to evaluate the proliferation and sensitivity to doxorubicin of cells in the MCF-7-miR-93 mimics group. The results revealed that the overexpression of miR-93 markedly upregulated the proliferation rate of MCF-7 cells (Fig. 2A; p<0.01), and also significantly increased the survival ratio of cells treated with doxorubicin for 24 h (Fig. 2B; p<0.05).

qRT-PCR was used to examine the expression levels of the multi-drug resistant-related genes MDR, MRP and BCRP in MCF-7 and MCF-7-miR-93 mimic cells. The results demonstrated that the expression levels of each of these genes were significantly higher in the MCF-7-miR-93 mimic cells than in the MCF-7 cells (Fig. 2C; p<0.01). Furthermore, flow cytometric analysis revealed that the rate of doxorubicin-induced apoptosis was lower in the MCF-7-miR-93 mimic cells than in untransfected MCF-7 cells (Fig. 3A, B and E; p<0.01). By contrast, in the MCF-7/ADR-miR-93 inhibitor cells, the rate of doxorubicin-induced apoptosis was significantly increased compared with that in the untransfected MCF-7/ADR-miR-93 cells (Fig. 3C, D, and F; p<0.01).

EMT in MCF-7 cells overexpressing miR-93

To explore the possible relationship between miR-93 expression and cancer cell EMT, the changes in morphological features and the mRNA levels of EMT-related genes were examined after the transfection of MCF-7 cells with miR-93 mimics or NC. The morphological features of the cells are shown in Fig. 4A. MCF-7-miR-93 mimic-transfected cells displayed a cobbleston-like appearance and tight cell-cell junctions. By contrast, the MCF-7-miR-93 mimic NC and untransfected MCF-7 cells appeared to have spindle-cell morphology. Meanwhile, the qRT-PCR results revealed that the expression level of the epithelial marker E-cadherin was markedly decreased, while the levels of the mesenchymal markers N-cadherin, vimentin, Twist, Snail and fibronectin were markedly increased after transfection with the miR-93 mimics (Fig. 4B; p<0.01).

Dual-luciferase reporter assay and qRT-PCR analysis of PTEN

To detect the possible association between miR-93 and PTEN, a ‘miRanda’ bioinformatics analysis was initially performed. The miRNA target prediction program indicated PTEN as one of the possible target genes of miR-93. In particular, the 3′-untranslated region (UTR) of PTEN mRNA contains a binding site for miR-93 (Fig. 5A). To confirm this, a dual-luciferase reporter assay was carried out. The results revealed that, compared with the control group (MCF-7-miR-93 mimic NC), transfection with the miR-93 mimics decreased the luciferase activity of the reporter construct containing the wild-type PTEN 3′-UTR (Fig. 5B; p<0.01), whereas the miR-93 mimics induced no significant change in the activity of the reporter construct containing the mutated PTEN 3′-UTR. This indicated that miR-93 can bind directly to the PTEN 3′-UTR. Furthermore, the qRT-PCR results confirmed that the miR-93 mimics could downregulate the expression level of PTEN in MCF-7 cells compared with the MCF-7-miR-93 mimics NC group (Fig. 5C; p<0.01).

Discussion

It has been widely reported that miRNAs are involved in numerous molecular events in various types of tumors (2123), including the acquisition of drug resistance, which is one of the most prominent clinical challenges at present. In the present study, miR-93 was selected for investigation as its function remains uncertain in many contexts, particularly in breast cancer. We aimed to clarify the role of miR-93 in the acquisition of drug resistance of breast cancer cells.

miR-93, along with miR-106b and miR-25, is a member of the miR-106b-25 cluster, which is located in its host gene, MCM7 (24). All members of the miR-106b-25 cluster, in addition to MCM7, have been reported to be involved in tumorigenesis (2527) and drug resistance (28,29) in multiple tumors. Furthermore, our previous study on miRNA profiles revealed that miR-93 was the most upregulated miRNA of this cluster in the doxorubicin-resistant MCF-7 cells compared with the parental MCF-7 cells, which indicated that miR-93 may be the major contributor to the drug resistance of breast cancer cells in this cluster. Simultaneously, in our preliminary experiments, we also tested the differential expression trends of MCM7 in MCF-7/ADR and MCF-7 cells, which revealed a less marked difference than that of miR-93. Therefore, miR-93, rather than the whole cluster and its host gene, may play a critical role in the acquisition of drug resistance in breast cancer. To date, very few studies have focused on the role of miR-93 in breast cancer (3036). Furthermore, these studies only reported its association with altered expression patterns and proliferation, and none have focused on its relationship with drug resistance and association with PTEN.

The results of the present study revealed a higher expression level of miR-93 in primary ductal breast cancer tissues than in corresponding tumor-adjacent normal tissues, and an increased proliferation rate in miR-93-overexpressing MCF-7 cells, which confirmed that miR-93 may be involved in the progression of breast cancer. Furthermore, a higher expression level of miR-93 was observed in MCF-7/ADR cells than in MCF-7 cells, and the survival ratio of miR-93-overexpressing MCF-7 cells following exposure to doxorubicin was increased markedly compared with that of the miR-93 mimics NC group. Furthermore, the expression levels of multi-drug resistance-related genes were significantly upregulated in the miR-93-overexpressing MCF-7 cells compared with NC-transfected cells, concomitant with the increase in doxorubicin resistance. In contrast, the miR-93 inhibitor treatment led to a reversal of doxorubicin resistance in the MCF-7/ADR cells. Thus, we suggest that miR-93 may contribute to the doxorubicin resistance of breast cancer cells.

EMT has been observed in the majority of tumors (37,38), and emerging evidence also indicates that it may be involved in drug resistance in certain types of cancer cells (7,39), including breast cancer (40,41). In the present study, the observed morphological changes and the upregulation of EMT-related genes in miR-93-overexpressing MCF-7 cells indicated that miR-93 participates in EMT in breast cancer cells. Moreover, the significant upregulation of drug resistance-related genes in the miR-93-overexpressing MCF-7 cells was observed concomitantly with EMT, which infers that EMT may be involved in the miR-93-induced drug resistance of breast cancer cells.

Following bioinformatics analysis and the retrieval of related literature (18), we speculated that PTEN may be a direct target gene of miR-93, and the results of a dual-luciferase reporter assay and the downregulation of PTEN in miR-93-overexpressing MCF-7 cells confirmed this direct interaction in breast cancer cells. The PI3K/Akt signaling pathway is considered to be one of the mechanisms underlying EMT in cancer cells, and PTEN has been shown to be a regulatory factor upstream of this pathway (42). Combined with our results, we hypothesize that miR-93 affects EMT through its interaction with PTEN, subsequently inducing drug resistance in breast cancer cells.

In conclusion, miR-93 may play an important role in EMT and drug resistance of breast cancer cells by targeting PTEN. The present study provides novel insights into the biological function of miR-93 in breast cancer drug resistance. miR-93 may be considered a potential biomarker of prognosis, and a promising therapeutic target for the reversal of drug resistance in patients with breast cancer.

References

1 

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Holohan C, Van Schaeybroeck S, Longley DB and Johnston PG: Cancer drug resistance: An evolving paradigm. Nat Rev Cancer. 13:714–726. 2013. View Article : Google Scholar : PubMed/NCBI

3 

Lamouille S, Subramanyam D, Blelloch R and Derynck R: Regulation of epithelial-mesenchymal and mesenchymal-epithelial transitions by microRNAs. Curr Opin Cell Biol. 25:200–207. 2013. View Article : Google Scholar : PubMed/NCBI

4 

Zaravinos A: The Regulatory Role of MicroRNAs in EMT and Cancer. J Oncol. 2015:8658162015. View Article : Google Scholar : PubMed/NCBI

5 

Li C, Song L, Zhang Z, Bai XX, Cui MF and Ma LJ: MicroRNA-21 promotes TGF-β1-induced epithelial-mesenchymal transition in gastric cancer through up-regulating PTEN expression. Oncotarget. 7:66989–67003. 2016. View Article : Google Scholar : PubMed/NCBI

6 

Li H, Zhang P, Sun X, Sun Y, Shi C, Liu H and Liu X: MicroRNA-181a regulates epithelial-mesenchymal transition by targeting PTEN in drug-resistant lung adenocarcinoma cells. Int J Oncol. 47:1379–1392. 2015. View Article : Google Scholar : PubMed/NCBI

7 

Brozovic A: The relationship between platinum drug resistance and epithelial-mesenchymal transition. Arch Toxicol. 91:605–619. 2017. View Article : Google Scholar : PubMed/NCBI

8 

Huang J, Li H and Ren G: Epithelial-mesenchymal transition and drug resistance in breast cancer (Review). Int J Oncol. 47:840–848. 2015.PubMed/NCBI

9 

Du B and Shim JS: Targeting epithelial-mesenchymal transition (EMT) to overcome drug resistance in cancer. Molecules. 21:pii: E965. 2016. View Article : Google Scholar

10 

Bugide S, Gonugunta VK, Penugurti V, Malisetty VL, Vadlamudi RK and Manavathi B: HPIP promotes epithelial-mesenchymal transition and cisplatin resistance in ovarian cancer cells through PI3K/AKT pathway activation. Cell Oncol. 40:133–144. 2016. View Article : Google Scholar

11 

Chen GQ, Zhao ZW, Zhou HY, Liu YJ and Yang HJ: Systematic analysis of microRNA involved in resistance of the MCF-7 human breast cancer cell to doxorubicin. Med Oncol. 27:406–415. 2010. View Article : Google Scholar : PubMed/NCBI

12 

Miao Y, Zheng W, Li N, Su Z, Zhao L, Zhou H and Jia L: MicroRNA-130b targets PTEN to mediate drug resistance and proliferation of breast cancer cells via the PI3K/Akt signaling pathway. Sci Rep. 7:419422017. View Article : Google Scholar : PubMed/NCBI

13 

Xia H, Ooi LL and Hui KM: MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer. Hepatology. 58:629–641. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Chen Q, Qin R, Fang Y and Li H: Berberine sensitizes human ovarian cancer cells to cisplatin through miR-93/PTEN/Akt signaling pathway. Cell Physiol Biochem. 36:956–965. 2015. View Article : Google Scholar : PubMed/NCBI

15 

Ke ZP, Xu P, Shi Y and Gao AM: MicroRNA-93 inhibits ischemia-reperfusion induced cardiomyocyte apoptosis by targeting PTEN. Oncotarget. 7:28796–28805. 2016. View Article : Google Scholar : PubMed/NCBI

16 

Fu X, Tian J, Zhang L, Chen Y and Hao Q: Involvement of microRNA-93, a new regulator of PTEN/Akt signaling pathway, in regulation of chemotherapeutic drug cisplatin chemosensitivity in ovarian cancer cells. FEBS Lett. 586:1279–1286. 2012. View Article : Google Scholar : PubMed/NCBI

17 

Jiang L, Wang C, Lei F, Zhang L, Zhang X, Liu A, Wu G, Zhu J and Song L: miR-93 promotes cell proliferation in gliomas through activation of PI3K/Akt signaling pathway. Oncotarget. 6:8286–8299. 2015. View Article : Google Scholar : PubMed/NCBI

18 

Ohta K, Hoshino H, Wang J, Ono S, Iida Y, Hata K, Huang SK, Colquhoun S and Hoon DS: MicroRNA-93 activates c-Met/PI3K/Akt pathway activity in hepatocellular carcinoma by directly inhibiting PTEN and CDKN1A. Oncotarget. 6:3211–3224. 2015. View Article : Google Scholar : PubMed/NCBI

19 

McCann MJ, Rowland IR and Roy NC: The anti-proliferative effects of enterolactone in prostate cancer cells: Evidence for the role of DNA licencing genes, mi-R106b cluster expression, and PTEN dosage. Nutrients. 6:4839–4855. 2014. View Article : Google Scholar : PubMed/NCBI

20 

Kawano M, Tanaka K, Itonaga I, Ikeda S, Iwasaki T and Tsumura H: microRNA-93 promotes cell proliferation via targeting of PTEN in Osteosarcoma cells. J Exp Clin Cancer Res. 34:762015. View Article : Google Scholar : PubMed/NCBI

21 

Shen J, Stass SA and Jiang F: MicroRNAs as potential biomarkers in human solid tumors. Cancer Lett. 329:125–136. 2013. View Article : Google Scholar : PubMed/NCBI

22 

Bertoli G, Cava C and Castiglioni I: MicroRNAs: New biomarkers for diagnosis, prognosis, therapy prediction and therapeutic tools for breast cancer. Theranostics. 5:1122–1143. 2015. View Article : Google Scholar : PubMed/NCBI

23 

An X, Sarmiento C, Tan T and Zhu H: Regulation of multidrug resistance by microRNAs in anti-cancer therapy. Acta Pharm Sin B. 7:38–51. 2017. View Article : Google Scholar : PubMed/NCBI

24 

Poliseno L, Salmena L, Riccardi L, Fornari A, Song MS, Hobbs RM, Sportoletti P, Varmeh S, Egia A, Fedele G, et al: Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation. Sci Signal. 3:ra292010. View Article : Google Scholar : PubMed/NCBI

25 

Petrocca F, Visone R, Onelli MR, Shah MH, Nicoloso MS, de Martino I, Iliopoulos D, Pilozzi E, Liu CG, Negrini M, et al: E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell. 13:272–286. 2008. View Article : Google Scholar : PubMed/NCBI

26 

Gong C, Qu S, Liu B, Pan S, Jiao Y, Nie Y, Su F, Liu Q and Song E: MiR-106b expression determines the proliferation paradox of TGF-β in breast cancer cells. Oncogene. 34:84–93. 2015. View Article : Google Scholar : PubMed/NCBI

27 

Chen S, Chen X, Xiu YL, Sun KX and Zhao Y: Inhibition of ovarian epithelial carcinoma tumorigenesis and progression by microRNA 106b mediated through the RhoC pathway. PLoS One. 10:e01257142015. View Article : Google Scholar : PubMed/NCBI

28 

Zhou Y, Hu Y, Yang M, Jat P, Li K, Lombardo Y, Xiong D, Coombes RC, Raguz S and Yagüe E: The miR-106b~25 cluster promotes bypass of doxorubicin-induced senescence and increase in motility and invasion by targeting the E-cadherin transcriptional activator EP300. Cell Death Differ. 21:462–474. 2014. View Article : Google Scholar : PubMed/NCBI

29 

Hu Y, Li K, Asaduzzaman M, Cuella R, Shi H, Raguz S, Coombes RC, Zhou Y and Yagüe E: MiR-106b~25 cluster regulates multidrug resistance in an ABC transporter-independent manner via downregulation of EP300. Oncol Rep. 35:1170–1178. 2016. View Article : Google Scholar : PubMed/NCBI

30 

Kolacinska A, Morawiec J, Pawlowska Z, Szemraj J, Szymanska B, Malachowska B, Morawiec Z, Morawiec-Sztandera A, Pakula L, Kubiak R, et al: Association of microRNA-93, 190, 200b and receptor status in core biopsies from stage III breast cancer patients. DNA Cell Biol. 33:624–629. 2014. View Article : Google Scholar : PubMed/NCBI

31 

McDermott AM, Miller N, Wall D, Martyn LM, Ball G, Sweeney KJ and Kerin MJ: Identification and validation of oncologic miRNA biomarkers for luminal A-like breast cancer. PLoS One. 9:e870322014. View Article : Google Scholar : PubMed/NCBI

32 

Hu J, Xu J, Wu Y, Chen Q, Zheng W, Lu X, Zhou C and Jiao D: Identification of microRNA-93 as a functional dysregulated miRNA in triple-negative breast cancer. Tumour Biol. 36:251–258. 2015. View Article : Google Scholar : PubMed/NCBI

33 

Liu S, Patel SH, Ginestier C, Ibarra I, Martin-Trevino R, Bai S, McDermott SP, Shang L, Ke J, Ou SJ, et al: MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells. PLoS Genet. 8:e10027512012. View Article : Google Scholar : PubMed/NCBI

34 

Singh B, Ronghe AM, Chatterjee A, Bhat NK and Bhat HK: MicroRNA-93 regulates NRF2 expression and is associated with breast carcinogenesis. Carcinogenesis. 34:1165–1172. 2013. View Article : Google Scholar : PubMed/NCBI

35 

Smith AL, Iwanaga R, Drasin DJ, Micalizzi DS, Vartuli RL, Tan AC and Ford HL: The miR-106b-25 cluster targets Smad7, activates TGF-β signaling, and induces EMT and tumor initiating cell characteristics downstream of Six1 in human breast cancer. Oncogene. 31:5162–5171. 2012. View Article : Google Scholar : PubMed/NCBI

36 

Fang L, Du WW, Yang W, Rutnam ZJ, Peng C, Li H, O'Malley YQ, Askeland RW, Sugg S, Liu M, et al: MiR-93 enhances angiogenesis and metastasis by targeting LATS2. Cell Cycle. 11:4352–4365. 2012. View Article : Google Scholar : PubMed/NCBI

37 

Yeung KT and Yang J: Epithelial-mesenchymal transition in tumor metastasis. Mol Oncol. 11:28–39. 2017. View Article : Google Scholar : PubMed/NCBI

38 

Xiang J, Fu X, Ran W and Wang Z: Grhl2 reduces invasion and migration through inhibition of TGFβ-induced EMT in gastric cancer. Oncogenesis. 6:e2842017. View Article : Google Scholar : PubMed/NCBI

39 

Dia VP and Pangloli P: Epithelial-to-mesenchymal transition in paclitaxel-resistant ovarian cancer cells is downregulated by luteolin. J Cell Physiol. 232:391–401. 2017. View Article : Google Scholar : PubMed/NCBI

40 

Preca BT, Bajdak K, Mock K, Lehmann W, Sundararajan V, Bronsert P, Matzge-Ogi A, Orian-Rousseau V, Brabletz S, Brabletz T, et al: A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer. Oncotarget. 8:11530–11543. 2017.PubMed/NCBI

41 

Liu G, Liu YJ, Lian WJ, Zhao ZW, Yi T and Zhou HY: Reduced BMP6 expression by DNA methylation contributes to EMT and drug resistance in breast cancer cells. Oncol Rep. 32:581–588. 2014. View Article : Google Scholar : PubMed/NCBI

42 

Larue L and Bellacosa A: Epithelial-mesenchymal transition in development and cancer: Role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene. 24:7443–7454. 2005. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

October 2017
Volume 38 Issue 4

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Chu, S., Liu, G., Xia, P., Chen, G., Shi, F., Yi, T., & Zhou, H. (2017). miR-93 and PTEN: Key regulators of doxorubicin-resistance and EMT in breast cancer. Oncology Reports, 38, 2401-2407. https://doi.org/10.3892/or.2017.5859
MLA
Chu, S., Liu, G., Xia, P., Chen, G., Shi, F., Yi, T., Zhou, H."miR-93 and PTEN: Key regulators of doxorubicin-resistance and EMT in breast cancer". Oncology Reports 38.4 (2017): 2401-2407.
Chicago
Chu, S., Liu, G., Xia, P., Chen, G., Shi, F., Yi, T., Zhou, H."miR-93 and PTEN: Key regulators of doxorubicin-resistance and EMT in breast cancer". Oncology Reports 38, no. 4 (2017): 2401-2407. https://doi.org/10.3892/or.2017.5859