Knockdown of miR-183 Enhances the Cisplatin-Induced Apoptosis in Esophageal Cancer Through Increase of FOXO1 Expression
Authors Chen H, Zheng B, Xue S, Chen C
Received 17 April 2020
Accepted for publication 11 June 2020
Published 24 August 2020 Volume 2020:13 Pages 8463—8474
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Tohru Yamada
Hao Chen, Bin Zheng, Songtao Xue, Chun Chen
Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou City, Fujian Province 350000, People’s Republic of China
Correspondence: Chun Chen No. 29, Xinquan Street, Gulou Distribution, Fuzhou City, Fujian Province 350000, People’s Republic of China
Email [email protected]
Background: As an important member of platinum-based chemotherapeutic drugs, cisplatin is effective and is commonly used in the treatment of esophageal cancer. However, repeated use of cisplatin usually causes severe side-effects on patients. Novel approaches should be explored to increase the sensitivity of cancer cells to cisplatin.
Methods: The expression level of miR-183 in esophageal cancer tissues and cell lines was measured by quantitative reverse transcriptase real-time PCR (qRT-PCR). The sensitivity of EC cell lines to cisplatin was evaluated by CCK-8 assay and flow cytometry. Luciferase reporter assay was used to confirm the association between miR-183 and FOXO1. The apoptosis pathway of EC cells was tested by Western blot assay.
Results: The expression level of miR-183 was increased in esophageal cancer patients’ tumor tissues and esophageal cancer cell lines. However, knockdown of miR-183 was found to enhance the effect of cisplatin on inducing the apoptotic cell death of esophageal cancer cells. In the mechanism research, we proved that FOXO1 was the target of miR-183 in esophageal cancer cells. Inhibition of miR-183 increased the expression of FOXO1 to promote the expression of Bim and Noxa. As Bim and Noxa acted as key pro-apoptotic proteins in mitochondrial apoptosis, inhibition of miR-183 enhanced the cisplatin-induced apoptosis pathway in esophageal cancer.
Conclusion: Knockdown of miR-183 enhanced the cisplatin-induced apoptosis in esophageal cancer through an increase of FOXO1 expression.
Keywords: cisplatin, miR-183, esophageal cancer, FOXO1
Esophageal cancer (EC) is the fourth most common gastrointestinal cancer and a leading cause of mortality in the world.1,2 Despite surgery being the most effective treatment for early stage and localized cancers, chemotherapy is the only option for patients with advanced EC to prolong their life.3,4 Cisplatin is an effective chemotherapeutic agent that is used for the treatment of EC.5,6 However, a substantial proportion of EC patients do not benefit from cisplatin because of the drug resistance.7,8 Mechanisms which determine cisplatin sensitivity in EC are required to be identified.
Cisplatin is a platinum-based drug that cross-links with DNAs and thus induces apoptotic cell death of cancer cells.9,10 However, EC cells usually develop some strategies to exhibit low sensitivity to cisplatin-induced apoptosis.11,12 Thus, reducing the resistance of EC cells to apoptosis signals is an important strategy for sensitizing the cisplatin treatment.
FOXO1 is a well-known tumor suppressor that regulates DNA repair and cell cycle transition.13,14 As an important transcription factor, FOXO1 facilitates cell apoptosis through promoting the transcriptional activities of Bim and Noxa which are the key pro-apoptotic proteins in the mitochondrial apoptosis pathway.15,16 Previous studies have reported that downregulation of FOXO1 induces tumorgenesis, cancer development, and chemoresistance.17,19 Therefore, FOXO1 is a potential target for improving the cancer therapy.
MicroRNAs (miRNAs) are endogenous RNAs with 19–25 nucleotides in length. Although miRNAs are single-stranded and non-coding, they function as gene suppressors through interaction with targeted mRNAs.20,21 Previous research has proved that dysregulation of miRNA is associated with tumorigenesis and tumor development, because numerous miRNA-regulated genes are involved in various physiological processes including cell proliferation, differentiation, metabolism, and apoptosis.22,23 Moreover, studies also demonstrate that aberrant expression of miRNA is responsible for drug resistance of various cancers.24,25 Among these deregulated miRNAs, miR-183 has been reported to be involved in tumor growth and is responsible for poor prognosis of cancer patients.26,27 However, the association between miR-183 and cisplatin sensitivity of EC is still unclear. In the present study, we mainly explored the role of miR-183 in cisplatin-induced apoptosis in esophageal cancer.
Materials and Methods
Cell Lines and Patients’ Specimens
EC and paired paracancerous tissues were obtained from 25 patients who underwent resection between April 2017 and May 2019 at Fujian Medical University Union Hospital. We have obtained written informed consent from all of the patients. The experimental protocols were approved by the ethics committee of Fujian Medical University Union Hospital (No. 2019-ZQN-64). Human EC cell lines EC9706 and TE-9 were cultured under the condition recommended by the vendor (Cell Bank of Shanghai Institute of Cell Biology, Shanghai, China). Cells were kept in a 5% CO2 incubator at 37°C.
Quantitative Reverse Transcriptase Real-Time PCR (qRT-PCR)
Relative expression of miR-183 and FOXO1 was measured by using qRT-PCR analysis. Briefly, total RNAs in EC patients’ resected tissues and cell lines were isolated by using Trizol Reagent (Life Technologies, Carlsbad, CA, USA) according to the manufacturer’s instruction. For detection of miR-183, cDNAs were synthesized with a One Step PrimeScript miRNA cDNA Synthesis Kit (TaKaRa, China). For detection of FOXO1, cDNA was synthesized by using M-MLV Reverse Transcriptase (Thermo Fisher Scientific, Inc.) following the manufacturer’s instruction. Subsequently, relative expression of miR-183 and FOXO1 was detected by using SYBR Premix Ex Taq (TaKaRa). Fold change of miR-183 was normalized to U6 snRNA and fold change of FOXO1 was normalized to GAPDH with the comparative cycle threshold method (2−ΔΔCT).
For enforced expression of FOXO1, the eukaryotic expression vector (pcDNA3.1 plasmid containing FOXO1 open reading frame; Thermo Fisher Scientific, Inc.) was conducted. Briefly, an open reading frame of FOXO1 gene was amplified by using the following primers: Forward, FOXO1 XhoI, 5ʹ-ATCTCGAGATGGCCGAGGCGCCTCAGGT-3ʹ, and reverse, FOXO1 BamHI, 5ʹ-ACGGATCCGCCTGACACCCAGCTATGTGTC-3ʹ. The recombinant pcDNA3.1 plasmid carrying FOXO1 open reading frame was named as FOXO1 plasmid. For luciferase reporter assay, the pMIR Firefly luciferase reporter with FOXO1 3ʹ UTR (pMIR-REPORT™ miRNA Expression Reporter Vector carrying wild type of FOXO1 3ʹ UTR fragment with the predicted miR-183 site; Ambion; Thermo Fisher Scientific, Inc.) was conducted. Briefly, a 3ʹ UTR fragment of FOXO1 gene was amplified by using the following primers: Forward, FOXO1 SpeI, 5ʹ-ACCGCATCGTGTGCTGCTGTAGATAAGG-3ʹ, and reverse, FOXO1 HindIII, 5ʹ-ACGAAGCTTTTGATAACAGGCTACTTGG-3ʹ. The recombinant pMIR Firefly luciferase reporter carrying wild type FOXO1 3ʹ UTR fragment was named as pMIR-FOXO1-wt. To mutate the seed region of the miR-183-binding sites (GUGCCAUU to GUGATAUU), the QuikChange Site-Directed Mutagenesis kit (Stratagene, Missouri, TEX, USA) was used based on the pMIR-FOXO1-wt following the manufacturer’s protocol. The conducted pMIR Firefly luciferase reporter carrying mutant type FOXO1 3ʹ UTR fragment was named as pMIR-FOXO1-mt.
FOXO1 plasmid, hsa-miR-183 mimic (miR-183), hsa-miR-183 antisense-oligonucleotide (anti-miR-183), negative control oligonucleotide (NCO) (GenePharma Co. Ltd, Shanghai, China), and FOXO1 siRNA (Santa Cruz Biotechnology, Santa Cruz, CA, USA) were transfected into cells by using Lipofectamine 2000 (Invitrogen, CA, USA) according to the manufacturer’s instruction. Twenty-four hours after transfection, cells were collected for the following experiments.
Cell Viability Assay
Transfected EC cells were seeded into 96-well plates. After cell adherence on plates, the corresponding cells were treated with medium containing cisplatin. After 48 hours incubation, cell viability was detected by CCK-8 according to the manufacturer’s instruction. The absorbance values of each well were determined by using a microplate reader (Sunrise Microplate Reader, TECAN, Switzerland). Results were expressed as the absorbance relative to the NCO group. Half inhibiting concentration (IC50) of cisplatin to EC9706 and TE-9 was evaluated according to the cell viability curve.
Luciferase Reporter Assay
Recombinant pMIR-reporter (2 μg/mL), renilla luciferase pRL-TK plasmid (100 ng/mL, Promega, USA) and miR-183 mimic (or anti-miR-183) were co-transfected into cells by using Lipofectamine 2000. Forty-eight hours after transfection, luciferase activities were measured by using a Dual-Luciferase Reporter assay system (Promega, Madison, WI, USA) according to the manufacturer’s instruction. Relative firefly luciferase activities were determined by normalization to Renilla luciferase activities in each well.
Western Blot Analysis
Protein samples were prepared and mixed with SDS loading buffer. Equal amounts of proteins were then electrophoresized by 10% SDS-PAGE and transferred to a PVDF membrane. Membranes were blocked in 5% non-fat milk before incubation with primary antibodies (Cell Signaling Technologies, Danvers, MA, USA). Subsequently, the membranes were washed and probed with appropriate secondary antibodies conjugated to horseradish peroxidase. Protein bands were detected by using an enhanced chemiluminescent substrate (Thermo Fisher Scientific, Inc.).
Cells were collected and washed twice with cold PBS. For detection of mitochondrial membrane potential (MMP, ΔΨ), cells were stained with 5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethyl imidacarbo cyanine iodide (JC-1, Molecular Probes; Waltham, MA, USA) as an indicator. Cells emitting red fluorescence were considered as cells with high MMP, and cells emitting green fluorescence were considered as cells with low MMP. For measurement of apoptotic rate, an Annexin V-FITC Apoptosis Detection Kit (Sigma Aldrich, St. Louis, MO, USA) was used according to the manufacturer’s instruction. The Annexin V-positive cells were considered as the apoptotic cells. All of the cells were analyzed by using FACSAria flow cytometry (BD Biosciences, San Jose, CA, USA).
In vivo Experiment
Anti-miR-183-EC9706 was conducted to stably express miR-183 antisense nucleotide sequence by using a lentiviral-based system (Genechem Co., Ltd., Shanghai, China). For tumourigenesis assays, 5×106 of anti-miR-183-EC9706 or control EC9706 cells were inoculated subcutaneously into the BALB/c nude mice (4~5 weeks old). After xenografts reached 0.5 cm in diameter, animals were treated with cisplatin i.p. twice a week (2 mg/kg) until the mice were killed 25 days post-injection. Subsequently, the tumors were taken out for the following experiments. Collagenase type III was used to purify the tumor tissue cells. The animal experiments were conducted in strict accordance with the Guide for the Care and Use of Laboratory Animals, 8th edition, issued by the National Institute of Health. Experiment protocols were approved by the ethics committee of Fujian Medical University Union Hospital (JN.No20190515S0150117).
Three independent experiments were performed to obtain the data. Data values were presented as means±standard deviation (SD). Statistical differences between groups were analyzed by One-way analysis of variance (ANOVA) using SPSS 15.0 software. Differences were considered significant when P-values were less than 0.05.
miR-183 is Overexpressed in EC Patients’ Tumor Tissues and Cell Lines
To investigate the potential role of miR-183 in EC, the expression levels of miR-183 in EC patients’ tumor tissues and cell lines were tested by using qRT-PCR analysis. As shown in Figure 1A, obviously a higher level of miR-183 was observed in EC patients’ tumor tissues compared to the paracancerous tissues. Furthermore, the expression level of miR-183 was found to be upregulated in EC9706 and TE-9 EC cell lines compared to the normal tissue cells and Het-1A which was human normal esophageal epithelial cell line (Figure 1B). These results suggested that an increase of miR-183 was a frequent event in EC.
Knockdown of miR-183 Increases the Sensitivity of EC Cells to Cisplatin
To explore the influence of miR-183-overexpression on the sensitivity of EC cells to cisplatin, we knocked down the miR-183 by using the miR-183 antisense-oligonucleotide (anti-miR-183). As shown in Figure 2A, transfection with anti-miR-183 significantly decreased the cellular level of miR-183 in EC9706 and TE-9 cell lines. Next, we treated the NCO-transfected or anti-miR-183-transfected EC9706 and TE-9 cells with cisplatin at the concentration of 1 μM, because 1 μM cisplatin just induced relatively slight cell death of EC9706 and TE-9 (Figure 2B). Results of the CCK-8 assay revealed that the anti-miR-183-transfected EC9706 and TE-9 EC cells exhibited obvious higher sensitivity to cisplatin compared to the NCO-transfected EC9706 and TE-9 cells (Figure 2B). To detect the effect of anti-miR-183 on changing the IC50 of cisplatin to EC cells, we treated the anti-miR-183-transfected EC9706 and TE-9 cells with different concentrations of cisplatin. We observed that anti-miR-183 can enhance the cytotoxicity of various concentrations of cisplatin against EC (Figure 2C). Specifically, IC50 of cisplatin to NCO-transfected EC9706 was 6.4-fold higher than that to anti-miR-183-transfected EC9706, and the IC50 of cisplatin to NCO-transfected TE-9 was 7.1-fold higher than that to anti-miR-183-transfected TE-9 (Figure 2D). These data indicated that knockdown of miR-183 can increase the sensitivity of EC cells to cisplatin.
Anti-miR-183 Sensitizes EC Cells to Cisplatin-Induced Apoptosis
To deeply investigate the role of anti-miR-183 in cisplatin treatment in EC, we next tested the apoptosis pathway. As shown in Figure 3A and B, under the treatment of equal concentration of cisplatin, apoptotic rate of anti-miR-183-transfected EC9706 and TE-9 cells was significantly higher than the NCO-transfected EC9706 and TE-9 cells. Furthermore, we found that transfection with anti-miR-183 promoted the collapse of mitochondrial membrane potential (MMP, ΔΨ) induced by cisplatin (Figure 3C). These data showed that transfection with anti-miR-183 can sensitize EC cells to cisplatin-induced apoptosis through the mitochondrial pathway.
FOXO1 is the Target of miR-183 in EC
To explain how anti-miR-183 promoted cisplatin-induced apoptosis, we next searched the potential mRNA target of miR-183 in EC cells. According to the public databases of TargetScan, miRanda, and PicTar, FOXO1, a reported tumor suppressor in multiple cancers,28,30 was commonly predicted to be the potential target of miR-183. The seed region of 3ʹUTR of FOXO1 mRNA paired with miR-183 is shown in Figure 4A. Contrary to the overexpression of miR-183 in EC tissues (Figure 1A), expression of FOXO1 was found to be decreased in EC tissues (Figure 4B). Furthermore, FOXO1 was overexpressed in EC cell lines at both the mRNA level (Figure 4C) and protein level (Figure 4D). We therefore speculated that FOXO1 might be the target of miR-183 in EC. After transfection with anti-miR-183 in EC9706 and TE-9, we observed that expression of FOXO1 was increased at the mRNA level (Figure 4E) and protein level (Figure 4F). Furthermore, results of luciferase reporter assay showed that co-transfection with miR-183 mimic decreased the luciferase activities of FOXO1 3ʹ UTR reporter in EC9706 and TE-9 cells. On the contrary, anti-miR-183 increased the luciferase activities of the FOXO1 3ʹ UTR reporter (Figure 4G). Taken together, we demonstrated that FOXO1 was the target of miR-183. Overexpression of miR-183 induced reduction of FOXO1 in EC.
Anti-miR-183 Enhances Cisplatin-Induced Cell Death Through the FOXO1 Pathway in EC
Given that FOXO1 was the target of miR-183, we next investigated whether the sensitization of anti-miR-183 on cisplatin was dependent on the upregulation of FOXO1. We thus co-transfected the EC9706 and TE-9 cells with FOXO1 siRNA to antagonize the effect of anti-miR-183. As shown in Figure 5A, FOXO1 siRNA suppressed the expression of FOXO1 in EC cells even though they were transfected with anti-miR-183. As a result, we found that FOXO1 siRNA significantly increased the cell viability of EC9706 and TE-9 cells which were co-treated with cisplatin and anti-miR-183 (Figure 5B). On the other hand, we directly increased the expression of FOXO1 through transfection with FOXO1 plasmid (Figure 5C). As a result, we found that treatment with FOXO1 plasmid also can enhance the cytotoxicity of cisplatin, similarly with anti-miR-183 (Figure 5D). Taken together, these data indicated that anti-miR-183 enhanced cisplatin-induced cell death through the FOXO1 pathway in EC.
Anti-miR-183 Sensitizes EC Cells to Cisplatin-Induced Apoptosis Through the FOXO1 Pathway
Bim and Noxa expression is directly transactivated by FOXO1.15,16 Given that, we next investigated the effect of anti-miR-183 on regulating the Bim and Noxa expression in cisplatin-treated EC cells. As shown in Figure 6A, despite the fact that anti-miR-183 cannot increase the expression of Bim and Noxa in cisplatin-free EC cells, it obviously promoted the expression of Bim and Noxa in cisplatin-treated EC cells. However, knockdown of FOXO1 by using FOXO1 siRNA abolished the effect of anti-miR-183 on Bim and Noxa. Bim and Noxa are important pro-apoptosis proteins that induce mitochondrial apoptosis.15,16 Given that, we tested the release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria. As shown in Figure 6B, we found that transfection with anti-miR-183 obviously increased the level of cytochrome c and AIF in cytosol of EC cells which were treated with cisplatin. Meanwhile, we also observed obvious activation of caspase-9 and caspase-3 in the cisplatin and anti-miR-183 co-treated EC cells (Figure 6C). However, knockdown of FOXO1 by using FOXO1 siRNA abolished the promotion of anti-miR-183 on the cisplatin-dependent apoptosis pathway of EC cells (Figure 6B and C). Taken together, we demonstrated that anti-miR-183 can sensitize EC cells to cisplatin-induced apoptosis through the FOXO1 pathway.
Knockdown of miR-183 Enhances the Anti-Tumor Effect of Cisplatin on EC in vivo
Control EC9706 or anti-miR-183-EC9706 were used to establish the human EC model on mice. We then found that the miR-183-inhibited EC tumors were more sensitive to cisplatin treatment compared to the control EC tumors (Figure 7A). Subsequently, we measured the expression of miR-183 and FOXO1 in the purified tumor tissues. We confirmed the knockdown of miR-183 in the anti-miR-183-EC9706 cells (Figure 7B). In contrast, the anti-miR-183-EC9706 tumors showed an obviously higher protein level of FOXO1. Furthermore, under the equal administration of cisplatin, the anti-miR-183-EC9706 tumors expressed a higher level of Bim and Noxa compared to the control tumors (Figure 7C). We thus demonstrated that knockdown of miR-183 can enhance the anti-tumor effect of cisplatin on EC in vivo.
Cisplatin is one kind of platinum-based drug that induces apoptotic cell death in a wide range of cancers such as breast cancer, pancreatic cancer, gastric cancer, ovarian cancer, lung cancer, and esophageal cancer.31,36 Despite cisplatin-based treatment being effective for EC, cisplatin-resistance is still a common incidence during the course of chemotherapy.37 Factors that determine cisplatin sensitivity of EC are required to be identified.
Recent studies have reported that the expression profile of miRNA is closely associated with chemosensitivity. MiRNAs function as chemoresistant modulators and can be considered as potential therapeutic targets during cisplatin therapy.38,39 Among these cancer-related miRNAs, miR-183 has been reported to be responsible for tumorigenesis and drug resistance in cancers including EC.26,27,40,41 Consistent with these previous reports, we observed significant upregulation of miR-183 in EC cell lines and patients' tumor tissues. Moreover, we found that the cellular level of miR-183 partially determined the sensitivity of cisplatin to EC cells. Our data indicated that treatment with miR-183 antisense-oligonucleotide can be considered as a promising adjuvant therapy in vitro and in vivo.
FOXO1 is a well-known tumor suppressor that inhibits the occurrence of chemoresistance of cancers. However, cancerous cells usually reduce the expression level of FOXO1 to promote the cell proliferation and inhibit the cell apoptosis.42,43 In this study, we also observed the significant downregulation of FOXO1 in EC cells. Furthermore, we proved that the absence of FOXO1 was responsible for the reduction of cisplatin sensitivity to EC. Thus, FOXO1 can be considered as a novel target for improving the chemotherapy of cancer.
In our mechanism research, we proved that downregulation of FOXO1 in EC cells was induced by overexpression of miR-183. Furthermore, our data indicated that suppression of miR-183 can significantly increase the expression of FOXO1. Subsequently, FOXO1 promoted the expression of Bim and Noxa which were pro-apoptotic proteins. Under the apoptotic signaling caused by cisplatin, Bim and Noxa enhanced the dysfunction of mitochondria. As a result, mitochondria-derived apoptotic inducers such as cytochrome c and AIF44,45 were released from mitochondria into the cytosol of EC cells. Eventually, caspases-dependent apoptosis was triggered (Figure 8). In summary, we proved that knockdown of miR-183 can enhance the cisplatin-induced apoptosis in esophageal cancer through an increase of FOXO1 expression. Intervention on the miR-183/FOXO1 axis may represent a promising strategy for improving the chemotherapy of cancers.
Thanks are due to the whole contributors who assisted with this study.
The authors report no conflicts of interest in this work.
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30. doi:10.3322/caac
2. Fatehi Hassanabad A, Chehade R, Breadner D, Raphael J. Esophageal carcinoma: towards targeted therapies. Cell Oncol (Dordr). 2020;43:195–209. doi:10.1007/s13402-019-00488-2
3. Kato H, Nakajima M. Treatments for esophageal cancer: a review. Gen Thorac Cardiovasc Surg. 2013;61:330–335. doi:10.1007/s11748-013-0246-0
4. Ku GY. Systemic therapy for esophageal cancer: chemotherapy. Chin Clin Oncol. 2017;6:49. doi:10.21037/cco.2017.07.06
5. Sawayama H, Ogata Y, Ishimoto T, et al. Glucose transporter 1 regulates the proliferation and cisplatin sensitivity of esophageal cancer. Cancer Sci. 2019;110:1705–1714. doi:10.1111/cas.13995
6. Zhang X, Jia J, Lu M, et al. Nimotuzumab plus paclitaxel and cisplatin as a 1st-line treatment for esophageal cancer: long term follow-up of a Phase II study. J Cancer. 2019;10:1409–1416. doi:10.7150/jca.28659
7. Wu K, Hu Y, Yan K, et al. microRNA-10b confers cisplatin resistance by activating AKT/mTOR/P70S6K signaling via targeting PPARγ in esophageal cancer. J Cell Physiol. 2020;235:1247–1258. doi:10.1002/jcp.29040
8. Wang J, Che W, Wang W, Su G, Zhen T, Jiang Z. CDKN3 promotes tumor progression and confers cisplatin resistance via RAD51 in esophageal cancer. Cancer Manag Res. 2019;11:3253–3264. doi:10.2147/CMAR.S193793
9. Zhang Y, Xie C, Li A, et al. PKI-587 enhances chemosensitivity of oxaliplatin in hepatocellular carcinoma through suppressing DNA damage repair pathway (NHEJ and HR) and PI3K/AKT/mTOR pathway. Am J Transl Res. 2019;11:5134–5149.
10. Seo SU, Min KJ, Woo SM, Kwon TK. Z-FL-COCHO, a cathepsin S inhibitor, enhances oxaliplatin-mediated apoptosis through the induction of endoplasmic reticulum stress. Exp Mol Med. 2018;50:107. doi:10.1038/s12276-018-0138-6
11. Shi H, Mao Y, Ju Q, et al. C-terminal binding protein‑2 mediates cisplatin chemoresistance in esophageal cancer cells via the inhibition of apoptosis. Int J Oncol. 2018;53:167–176. doi:10.3892/ijo.2018.4367
12. Wang Y, Pan T, Li L, et al. Knockdown of TGIF attenuates the proliferation and tumorigenicity of EC109 cells and promotes cisplatin-induced apoptosis. Oncol Lett. 2017;14:6519–6524. doi:10.3892/ol.2017.7009
13. Greer EL, Brunet A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 2005;24:7410–7425. doi:10.1038/sj.onc.1209086
14. Zhao Z, Qin L, Li S. miR-411 contributes the cell proliferation of lung cancer by targeting FOXO1. Tumour Biol. 2016;37:5551–5560. doi:10.1007/s13277-015-4425-8
15. Cao D, Di M, Liang J, Shi S, Tan Q, Wang Z. MicroRNA-183 in cancer progression. J Cancer. 2020;11:1315–1324. doi:10.7150/jca.39044
16. Li H, Pan X, Gui Y, et al. Upregulation of miR-183-5p predicts worse survival in patients with renal cell cancer after surgery. Cancer Biomark. 2019;24:153–158. doi:10.3233/CBM-182047
17. Goto T, Takano M, Hirata J, Tsuda H. The involvement of FOXO1 in cytotoxic stress and drug-resistance induced by paclitaxel in ovarian cancers. Br J Cancer. 2008;98:1068–1075. doi:10.1038/sj.bjc.6604279
18. Lang C, Xu M, Zhao Z, Chen J, Zhang L. MicroRNA-96 expression induced by low-dose cisplatin or doxorubicin regulates chemosensitivity, cell death and proliferation in gastric cancer SGC7901 cells by targeting FOXO1. Oncol Lett. 2018;16:4020–4026. doi:10.3892/ol.2018.9122
19. Qin Y, Li L, Wang F, et al. Knockdown of Mir-135b sensitizes colorectal cancer cells to oxaliplatin-induced apoptosis through increase of FOXO1. Cell Physiol Biochem. 2018;48:1628–1637. doi:10.1159/000492284
20. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–297. doi:10.1016/s0092-8674(04)00045-5
21. Farazi TA, Hoell JI, Morozov P, Tuschl T. MicroRNAs in human cancer. Adv Exp Med Biol. 2013;774:1–20. doi:10.1007/978-94-007-5590-1_1
22. Calin GA, Sevignani C, Dumitru CD, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A. 2004;101:2999–3004. doi:10.1073/pnas.0307323101
23. Schmittgen TD. Regulation of microRNA processing in development, differentiation and cancer. J Cell Mol Med. 2008;12:1811–1819. doi:10.1111/j.1582-4934.2008.00483.x
24. He H, Tian W, Chen H, Jiang K. MiR-944 functions as a novel oncogene and regulates the chemoresistance in breast cancer. Tumour Biol. 2016;37:1599–1607. doi:10.1007/s13277-015-3844-x
25. Liu J, Tang Q, Li S, Yang X. Inhibition of HAX-1 by miR-125a reverses cisplatin resistance in laryngeal cancer stem cells. Oncotarget. 2016;7:86446–86456. doi:10.18632/oncotarget.13424
26. Zhang B, Gui LS, Zhao XL, Zhu LL, Li QW. FOXO1 is a tumor suppressor in cervical cancer. Genet Mol Res. 2015;14:6605–6616. doi:10.4238/2015.June.18.3
27. Zhang L, Quan H, Wang S, Li X, Che X. MiR-183 promotes growth of non-small cell lung cancer cells through FoxO1 inhibition. Tumour Biol. 2015;36:8121–8126. doi:10.1007/s13277-015-3550-8
28. Yu JJ, Wu YX, Zhao FJ, Xia SJ. miR-96 promotes cell proliferation and clonogenicity by down-regulating of FOXO1 in prostate cancer cells. Med Oncol. 2014;31:910. doi:10.1007/s12032-014-0910-y
29. Chi HC, Chen SL, Cheng YH, et al. Chemotherapy resistance and metastasis-promoting effects of thyroid hormone in hepatocarcinoma cells are mediated by suppression of FoxO1 and Bim pathway. Cell Death Dis. 2016;7:e2324. doi:10.1038/cddis.2016.227
30. Valis K, Prochazka L, Boura E, et al. Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a FoxO1-dependent manner. Cancer Res. 2011;71:946–954. doi:10.1158/0008-5472.CAN-10-2203
31. Zhang J, Xie T. Ghrelin inhibits cisplatin-induced MDA-MB-231 breast cancer cell apoptosis via PI3K/Akt/mTOR signaling. Exp Ther Med. 2020;19:1633–1640. doi:10.3892/etm.2019.8398
32. Kong F, Liu X, Zhou Y, et al. Downregulation of METTL14 increases apoptosis and autophagy induced by cisplatin in pancreatic cancer cells. Int J Biochem Cell Biol. 2020;122:105731. doi:10.1016/j.biocel.2020.105731
33. Tian H, Wang W, Meng X, et al. ERas enhances resistance to cisplatin-induced apoptosis by suppressing autophagy in gastric cancer cell. Front Cell Dev Biol. 2020;7:375. doi:10.3389/fcell.2019.00375
34. Dai Y, Zhao XJ, Li F, et al. Truncated bid regulates cisplatin response via activation of mitochondrial apoptosis pathway in ovarian cancer. Hum Gene Ther. 2020;31:325–338. doi:10.1089/hum.2019.206
35. Jiang W, Zhao X, Yang W. MiR-647 promotes cisplatin-induced cell apoptosis via downregulating IGF2 in non-small cell lung cancer. Minerva Med. 2019. doi:10.23736/S0026-4806.19.06240-2
36. Yu X, Li W, Xia Z, et al. Targeting MCL-1 sensitizes human esophageal squamous cell carcinoma cells to cisplatin-induced apoptosis. BMC Cancer. 2017;17:449. doi:10.1186/s12885-017-3442-y
37. Hou S, Jin W, Xiao W, et al. Integrin α5 promotes migration and cisplatin resistance in esophageal squamous cell carcinoma cells. Am J Cancer Res. 2019;9:2774–2788.
38. Xiang Y, Chen YJ, Yan YB, et al. MiR-186 bidirectionally regulates cisplatin sensitivity of ovarian cancer cells via suppressing targets PIK3R3 and PTEN and upregulating APAF1 expression. J Cancer. 2020;11:3446–3453. doi:10.7150/jca.41135
39. Zhu H, Yang J, Yang S. MicroRNA-103a-3p potentiates chemoresistance to cisplatin in non-small cell lung carcinoma by targeting neurofibromatosis 1. Exp Ther Med. 2020;19:1797–1805. doi:10.3892/etm.2020.8418
40. Wang XJ, Zhang DL, Fu C, Wei BZ, Li GJ. MiR-183 modulates multi-drug resistance in hepatocellular cancer (HCC) cells via miR-183-IDH2/SOCS6-HIF-1α feedback loop. Eur Rev Med Pharmacol Sci. 2016;20:2020–2027.
41. Yang M, Liu R, Xiajun L, et al. miRNA-183 suppresses apoptosis and promotes proliferation in esophageal cancer by targeting PDCD4. Mol Cells. 2014;37(12):873–880. doi:10.14348/molcells.2014.0147
42. Wang Q, Yang X, Zhou X, et al. MiR-3174 promotes proliferation and inhibits apoptosis by targeting FOXO1 in hepatocellular carcinoma. Biochem Biophys Res Commun. 2020;S0006–291X(20):30645–30649. doi:10.1016/j.bbrc.2020.03.152
43. Zhang J, Zhang J, Zhang D, Ni W, Xiao H, Zhao B. Down-regulation of LINC00472 promotes osteosarcoma tumorigenesis by reducing FOXO1 expressions via miR-300. Cancer Cell Int. 2020;20:100. doi:10.1186/s12935-020-01170-6
44. Zhou Z, Zhu C, Cai Z, et al. Betulin induces cytochrome c release and apoptosis in colon cancer cells via NOXA. Oncol Lett. 2018;15:7319–7327. doi:10.3892/ol.2018.8183
45. He Y, Li B, Zhang H, et al. L-asparaginase induces in AML U937 cells apoptosis via an AIF-mediated mechanism. Front Biosci (Landmark Ed). 2014;19:515–527. doi:10.2741/4222
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Download Article [PDF]