Downregulation of thymopoietin by miR‑139‑5p suppresses cell proliferation and induces cell cycle arrest/apoptosis in pancreatic ductal adenocarcinoma
Retraction in: /10.3892/ol.2024.14623
- Authors:
- Published online on: July 29, 2019 https://doi.org/10.3892/ol.2019.10679
- Pages: 3443-3452
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Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Pancreatic ductal adenocarcinoma (PDAC) accounts for 80–90% of all cases of pancreatic cancer and is an epithelial malignancy that originates from the cells of the ducts or ductules (1,2). It is well known that PDAC can disseminate rapidly to the lymphatic system and distant organs (3). In previous reports, 43,090 cases of pancreatic cancer-associated mortality were predicted to occur in the United States in 2017, and it is gradually becoming the second leading cause of cancer-associated mortality (4,5). At present, surgical resection, radiochemotherapy and molecular-targeted therapy are considered to be effective treatments for patients with PDAC. However, almost all patients have a typical clinical presentation of incurable disease at the time of diagnosis (3). In addition, the 5-year survival rates remain at a steady rate of <8% (4,6). A previous etiological study (7) suggests that the development of PDAC is spurred on by genetic and epigenetic events.
Numerous short, non-coding RNAs (ranging between 19 and 24 nt in length), collectively named microRNAs (miRNAs), are now regarded as key components of the epigenetic machinery (8). The regulation of endogenous gene expression by miRNAs is an important mechanism in the pathogenesis and progression of human malignancies (9). In mammals, miRNAs are considered to inhibit gene expression through post-transcriptional regulation via mRNA decay and/or translational repression in a sequence-specific manner (10). In recent years, the aberrant expression of miRNAs has been found to serve a critical role in various fundamental biological and pathological processes, including proliferation, differentiation, inflammation, apoptosis and stress response (11). miR-139-5p, a member of the miRNA family, is located on chromosome 11q13.4 (12). Previous studies have shown that miR-139-5p is an epigenetically silenced tumor suppressor miRNA in bladder cancer (13), lung cancer (14), hepatocellular carcinoma (15) and colorectal cancer (16). By contrast, miR-139-5p exerts pro-oncogenic and pro-metastatic activities in adrenocortical cancer cells though negatively regulating the expression of NDRG4 (17). Li et al (18) recently reported that reduced miR-139-5p levels are associated with the pro-survival effect of liraglutide on pancreatic tissues in diabetic rats and INS-1 cells. However, the role and underlying mechanism of miR-139-5p in human PDAC remain to be fully elucidated. Thymopoietin (TMPO), also known as lamina-associated protein (LAP2), is an inner nuclear membrane protein that has six alternatively spliced isoforms (19). It has been suggested that a complex of TMPO and lamin A/C modulates multiple signaling pathways that balance proliferation and differentiation (20). The interplay between TMPO and barrier-to-autointegration factor in a sequence-independent manner may affect the stabilization of chromatin structure (21). TMPO has been identified as an oncogene in several types of cancer, including breast cancer, lung cancer and glioblastoma (22). Specifically, the regulation of cell motility, proliferation, cell cycle distribution and apoptosis have been described for TMPO in a various types of digestive tract cancer, glioblastoma and/or other types of cancer (22,23). However, whether TMPO serves an important role in PDAC and is regulated by miR-139-5p remains unclear.
The present study evaluated patterns of miR-139-5p expression in tumor tissues and tumor cell lines from patients with PDAC, and attempted to identify PDAC-associated miRNAs. The oncogene TMPO, a potential target of miR-139-5p, was revealed using bioinformatics resources. Furthermore, the biological function of the identified miR-139-5p/TMPO axis was determined to clarify the molecular mechanisms implicated in the progression and tumor biology of PDAC.
Materials and methods
Human tissue samples
A total of 40 pairs of fresh human PDAC tissues and adjacent matched non-tumor tissues were obtained from patients between August 2016 and October 2017 in the Department of Hepatobiliary Pancreatic Surgery, Renmin Hospital, Hubei University of Medicine (Hubei, China). Prior to tissue collection, it was confirmed that no patients had received chemotherapy or radiation therapy, and informed consent was obtained from all patients. Patient information, including age, sex, tumor size, pTNM category and differentiation, are summarized in Table I. The tumors were staged according to the American Cancer Association TNM staging system (2010) (24). The collected tissue samples were immediately snap-frozen in liquid nitrogen and stored at −80°C until processed. The present study was approved by the Human Ethics Review Committee of Renmin Hospital, Hubei University of Medicine.
Cell lines and culture
The human PDAC cell lines (SW1990, ASPC-1, BXPC-3 and PANC-1) and the HPNE human pancreatic duct epithelial cell line were purchased from the American Type Culture Collection (Manassas, VA, USA). The SW1990, PANC-1 and HPNE cell lines were cultured in Dulbecco's modified Eagle's medium (DMEM, Gibco; Thermo Fisher Scientific, Inc., Waltham, MA, USA). The ASPC-1 and BXPC-3 were grown in RPMI-1640 medium (Gibco; Thermo Fisher Scientific, Inc.). All media were supplemented with 10% fetal bovine serum (FBS), 100 IU/ml penicillin and 100 µg/ml streptomycin (Gibco; Thermo Fisher Scientific, Inc.). All cell lines were maintained in a humidified incubator containing 5% CO2 at 37°C.
RNA extraction and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis
Total RNA was extracted from the patient tissues or cells using RNAiso (Takara Biotechnology Co., Ltd., Dalian, China). The complementary DNA was synthesized using PrimeScript™ RT Reagent kit (Takara Biotechnology Co., Ltd.) according to the manufacturer's instructions. For the miR-139-5p quantitative assay, the Hairpin-it™ miRNA qPCR Quantitation kit (GenePharma Co., Ltd., Shanghai, China) was used to evaluate the expression of miR-139-5p, with U6 as an internal control. For the TMPO mRNA quantitative assay, the mRNA expression level of TMPO was determined using SYBR Green Premix Ex Taq (Takara Biotechnology, Co., Ltd.) with GAPDH as the internal control. The qPCR amplification was performed using an ABI 7900 Real-Time PCR system (Applied Biosystems; Thermo Fisher Scientific, Inc.) using the following the thermocycling conditions: initial denaturation at 95°C for 10 min and 40 cycles of 95°C for 15 sec, and 60°C for 1 min. The relative expression of miR-139-5p or TMPO was calculated using the 2−ΔΔCq method (25). The primer sequences for miR-139-5p, U6, TMPO and GAPDH are listed in Table II.
Cell transfection
The miR-139-5p mimics (5′-UAAGAUACUUAUGGCUUUGUGAA-3′) and the negative control (miR-NC; 5′-UAAGAUGACUAUGGCUUUGCUGA-3′) were obtained from Guangzhou RiboBio Co., Ltd. (Guangzhou, China). The pcDNA3.1-TMPO and pcDNA3.1 empty vector were synthesized by Shanghai GeneChem Co., Ltd. (Shanghai, China). Prior to transfection, the SW1990 and PANC-1 cells were seeded in six-well plates at a density of 4×105 cells per well. For the overexpression of miR-139-5p, the SW1990 and PANC-1 cells were transfected with miR-139-5p mimics or miR-NC to generate the miR-139-5p group and miR-NC group, respectively. In the rescue experiment, the SW1990 cells were transfected with sole pcDNA3.1 empty vector, pcDNA3.1-TMPO, or together with miR-139-5p and vector or pcDNA3.1-TMPO, respectively for 48 h, followed by subsequently experiments. All transfections were performed using Lipofectamine™ 2000 reagent (Invitrogen; Thermo Fisher Scientific, Inc.).
Bioinformatics analysis
The online software programs of miRanda (http://www.microrna.org/microrna/home.do), miRDB (http://www.mirdb.org/), PicTar (http://pictar.mdc-berlin.de/) and TargetScan (http://www.targetscan.org/vert_71/) were searched to predict the putative target genes of miR-139-5p.
Luciferase reporter assay
The psiCHECK-2 luciferase reporter plasmid containing the wild-type (WT) or mutant type (MUT) TMPO was generated by Guangzhou RiboBio Co., Ltd.. For the luciferase reporter assay, the SW1990 and PANC-1 cells were co-transfected with miR-139-5p mimics or miR-NC together with WT TMPO or MUT TMPO for 48 h using Lipofectamine 2000, according to the manufacturer's protocol. Subsequently, the luciferase activity was determined using a dual-luciferase reporter assay kit (Promega Corporation, Madison, WI, USA).
Western blot analysis
The transfected cells were washed with PBS and incubated in lysis buffer with protease inhibitor (Pierce; Thermo Fisher Scientific, Inc.), and protein concentrations were determined using a BCA Protein Assay kit (Beyotime Institute of Biotechnology, Beijing, China). Equal quantities of protein (30 µg) were separated on 10% SDS-PAGE gels and transferred onto polyvinylidene difluoride membranes. The membranes were blocked in TBS/0.1% Tween containing 5% BSA (Beyotime Institute of Biotechnology) at room temperature, followed by incubation with primary antibodies against TMPO (1:1,000; cat. no. ab226348; Abcam, Cambridge, UK) and GAPDH (1:5,000, cat. no. 10494-1-AP, ProteinTech Group, Inc., Chicago, IL USA) overnight at 4°C. Following incubation with horseradish peroxidase-conjugated secondary antibody (1:5,000; cat. no. SC-2054; Santa Cruz Biotechnology, Inc., Dallas, TX, USA) for 2 h at room temperature, the protein bands were visualized using an Enhanced Chemiluminescence Western Blotting kit (EMD Millipore, Billerica, MA, USA) and quantified using Image-pro plus 6.0 software (National Institutes of Health).
Cell Counting Kit-8 (CCK-8) assay
A CCK-8 assay (Beyotime Institute of Biotechnology) was used to determine cell proliferation. In brief, cells from the different groups were seeded at a density of 3×103 cells in 96-well plates and cultured overnight at 37°C. Subsequently, 10 µl CCK-8 reagents were added to each well on 5 consecutive days and each well was incubated for a further 2 h at 37°C. Finally, the absorbance at 450 nm was measured using a microplate reader (Epoch, BioTek Instruments, Inc., Winooski, VT, USA).
Colony formation assay
The transfected cells were seeded in 6-well plates at a density of 500 cells per well and cultured for 10 days to form colonies naturally. The colonies were then fixed in 4% paraformaldehyde, subsequently stained with 1% crystal violet at room temperature for 20 min, and then counted under a light microscope (magnification, ×200).
Cell cycle analysis
The transfected cells were collected, washed with pre-cooled PBS and fixed in 70% alcohol. Following washing twice with PBS, the cells were centrifuged at 500 × g at 4°C for 5 min to collect the precipitate, followed by incubation with 500 µl PBS containing 50 µg/ml propidium iodide (PI, Nanjing KeyGen Biotech Co., Ltd., Nanjing, China) solution and 100 µg/ml RNase for 30 min at room temperature. Finally, the cells were analyzed for their percentages at the G0/G1, S and G2/M phases by flow cytometry (BD Biosciences, San Jose, CA, USA).
Analysis of cell apoptosis
The transfected cells were collected and seeded into 6-well plates (3×105/well). The samples were subsequently digested in EDTA-free trypsin (Beyotime Institute of Biotechnology) and stained with 5 µl Annexin V-FITC and 5 µl PI (20%; Invitrogen; Thermo Fisher Scientific, Inc.) in the dark for 15 min at room temperature. The percentage of apoptotic cells, including early apoptosis and late apoptosis was measured by flow cytometry (BD Biosciences).
Statistical analysis
Data were analyzed using SPSS statistical software 18.0 (IBM Corp., Armonk, NY, USA) and expressed as the mean ± standard deviation from at least three independent experiments. Statistical difference between two groups or multiple groups were evaluated using Student's t-test or one-way analysis of variance followed by Dunnett's test, respectively. The association between the expression of TMPO and miR-139-5p in PDAC tissues was determined by Spearman's correlation analyses. P<0.05 was considered to indicate a statistically significant difference.
Results
miR-139-5p is downregulated in PDAC tissues and cell lines
To examine the biological function of miR-139-5p in PDAC, RT-qPCR analysis was first performed to examine the expression of miR-139-5p in 40 pairs of human PDAC tissues and matched adjacent normal tissues. As shown in Fig. 1A, the expression levels of miR-139-5p were significantly lower in the PDAC tissues than in the matched adjacent normal tissues (P<0.001). Subsequently, the expression levels of miR-139-5p were analyzed and compared between several PDAC cell lines and the normal HPNE pancreatic duct epithelial cell line. The results showed that the expression of miR-139-5p was markedly downregulated in all PDAC cell lines (SW1990, ASPC-1, BXPC-3 and PANC-1) compared with that in the HPNE cells (Fig. 1B). These data indicated that downregulated miR-139-5p may be a critical regulator in the progression of PDAC.
TMPO is a direct target of miR-139-5p
Using online bioinformatics analysis, TMPO was predicted to be a target gene of miR-139-5p and the binding sites are shown in Fig. 2A. Luciferase reporter assays were then performed to confirm whether miR-139-5p directly targeted TMPO. The results revealed that miR-139-5p significantly reduced the luciferase activity of a TMPO-3′-untranslated region (3′-UTR) WT reporter plasmid, but did not affect the luciferase activity of a TMPO-3′-UTR MUT reporter in SW1990 (Fig. 2B) and PANC-1 (Fig. 2C) cells. In addition, the mRNA and protein expression levels of TMPO were determined in SW1990 and PANC-1 cells under the regulation of miR-139-5p. As shown in Fig. 2D and E, the overexpression of miR-139-5p downregulated the expression of TMPO in SW1990 and PANC-1 cells at the mRNA (P<0.01) and protein (P<0.001) levels. These results suggested that TMPO was as a direct target gene of miR-139-5p in PDAC cells.
TMPO is overexpressed in PDAC and inversely correlated with miR-139-5p
As TMPO is a target of miR-139-5p in PDAC cells, the present study subsequently investigate the expression of TMPO in 40 pairs of human PDAC tissues and matched adjacent normal tissues using RT-qPCR analysis. As presented in Fig. 3A, the expression of TMPO was significantly upregulated in the PDAC tissues compared with that in the adjacent normal tissues (P<0.001). Notably, the expression level of miR-139-5p was inversely associated with the expression of TMPO in the 40 paired PDAC specimens (Fig. 3B, r=−0.5507, P=0.0002). In addition, RT-qPCR analysis revealed that the expression of TMPO was higher in the PDAC cell lines compared with that in the HPNE cell line (Fig. 3C, P<0.001), which was consistent with the results of the western blot analysis (Fig. 3D). These observations indicated that TMPO was frequently overexpressed in PDAC.
miR-139-5p affects cell proliferation, cell cycle and apoptosis in PDAC cells
To investigate the functional role of miR-139-5p in PDAC cells, SW1990 and PANC-1 cells were selected for gain-of-function assays as they had the lowest expression levels of miR-139-5p of the four PDAC cell lines. The efficiency of transfection was validated by RT-qPCR analysis, and the results showed that miR-139-5p was significantly upregulated in SW1990 and PANC-1 cells from the miR-139-5p group compared with those in the miR-NC group (Fig. 4A, P<0.001). The results of the CCK-8 assay showed that the proliferative ability was significantly suppressed in the miR-139-5p group compared with that in the miR-NC group in both SW1990 and PANC-1 cells (Fig. 4B, P<0.001). The colony formation ability of the PDAC cells was further examined. As shown in Fig. 4C, the number of colonies was significantly lower in the miR-139-5p group than in the miR-NC group in the SW1990 and PANC-1 cells (P<0.001).
Furthermore, the regulation of miR-139-5p on cell cycle distribution and apoptosis was analyzed using flow cytometry. As depicted in Fig. 5A, miR-139-5p transfection significantly increased the population of cells in the G0/G1 phase (SW1990: 67.38±0.31 vs. 49.82±0.38%, P<0.001; PANC-1: 52.92±0.49 vs. 49.48±0.47%, P<0.001) and decreased the population in the S phase (SW1990: 10.90±0.42 vs. 26.12±0.74%, P<0.001; PANC-1: 36.08±1.00 vs. 40.25±0.58%, P<0.01) and G2/M phase (SW1990: 21.72±0.70 vs. 24.06±1.02%, P<0.05) compared with populations in the miR-NC transfection group. This suggested that cell cycle was arrested at the G0/G1 phase by the overexpression if miR-139-5p. As shown in Fig. 5B, the overexpression of miR-139-5p markedly elevated the percentages of early apoptotic cells (SW1990: 10.59±0.40 vs. 2.08±0.15%, P<0.01; PANC-1: 13.82±0.51 vs. 7.66±0.20%, P<0.01) and late apoptotic cells (SW1990: 19.59±0.38 vs. 3.43±0.08%, P<0.001; PANC-1: 9.73±0.28 vs. 2.62±0.07%, P<0.01) compared with those in the miR-NC group. These results revealed that the overexpression of miR-139-5p exerted a potent apoptotic effect in PDAC cells.
Overexpression of TMPO partially eliminates the effects of miR-139-5p on cell proliferation, cell cycle and apoptosis in PDAC cells
To further investigate the role of TMPO in miR-139-5p-mediated cell proliferation, cell cycle arrest and apoptosis in PDAC cells, it was first confirmed that pcDNA3.1-TMPO was successfully transfected into SW1990 cells by RT-qPCR analysis (Fig. 6A, P<0.001). In addition, TMPO was overexpressed in SW1990/miR-139-5p mimics cells, as confirmed by RT-qPCR analysis (Fig. 6A, P<0.001) and western blot analysis (Fig. 6B, P<0.001). The CCK-8 assay revealed that the ectopic expression of TMPO effectively reversed the inhibition of proliferation induced by the overexpression of miR-139-5p in SW1990 cells (Fig. 6C). Consistently, the overexpression of TMPO alleviated the effects of miR-139-5p-induced cell cycle G0/G1 phase arrest (Fig. 6D) and apoptosis (Fig. 6E) in SW1990 cells. These results demonstrated that the anti-proliferative effects of miR-139-5p in PDAC cells may be mediated through TMPO.
Discussion
miRNAs are assigned as part of the epigenetic machinery and have been highlighted as critical regulators of gene expression (26). Aside from DNA methylation and histone modifications, the biological function and molecular mechanisms of miRNA-target interactions are of particular interest to the scientific community (27). Epigenetic modifications have been shown to be involved in the onset and development of numerous diseases and can contribute to explaining the clinical fluctuation of symptoms (28).
The aberrant expression of miR-139-5p in cancer is frequently reported and linked to the regulation of oncogenic and/or tumor suppressor genes. The present study revealed critical findings concerning the biological role of miR-139-5p in the progression of human PDAC. Firstly, the expression of miR-139-5p was found to be markedly downregulated in PDAC tissues and cell lines compared with that in adjacent tissues and pancreatic duct epithelial cells. To further analyze the functional role of miR-139-5p in PDAC, its potential gene targets were assessed. A bioinformatic screen identified TMPO is a potential target of miR-139-5p, the TMPO 3′-UTR and miR-139-5p 5′-UTR crosstalk was then confirmed using a luciferase reporter assay. Mechanically, the enforced expression of miR-139-5p decreased PDAC cell proliferation and induced G0/G1 arrest and apoptosis through negatively regulating TMPO, which indicated an antitumor effect of miR-139-5p in PDAC. MiR-139-5p is also a positive regulator of human colorectal cancer recurrence and metastasis; the hyperexpression of miR-139-5p was found to trigger peritoneal dissemination in a mouse tumor model (29). By contrast, emerging evidence indicates that miR-139-5p often acts as a tumor suppressor to regulate cellular events, including proliferation, aggressiveness and apoptosis, in tumor development and progression (12). These studies have revealed the tissue-specific epigenetic regulation of miR-139-5p in cancer.
TMPO is a chromatin-associated protein that interacts with A/B/C-type lamins, and localizes along the inner nuclear membrane of the nuclear envelope (30). The common N-terminal LAP2-Emerin-MAN1-domain (LEM-D) and a motif like LEM-D enable the binding between TMPO and chromosome to promote DNA replication through altering chromatin structure (31). LAP2α, a specific isoform of TMPO, can form a complex with lamin A/C at their C-terminal tails to reduce fibroblast proliferation via the retinoblastoma protein-linked pathways (32). The oncogenic role of TMPO was also identified in glioblastoma cells; TMPO deficiency depressed tumor cell proliferation, and induced cell cycle arrest and apoptosis (22). Consistently, the present study demonstrated that transfection of pcDNA3.1-TMPO alleviated the effects of miR-139-5p-induced growth inhibition, cell cycle G0/G1 phase arrest and apoptosis in PDAC cells.
In conclusion, the present study demonstrated for the first time, to the best of our knowledge, that the miR-139-5p/TMPO complex is an important regulator of the pathogenesis of PDAC; however, clinicopathological analysis of the expression of miR-139-5p and TMPO in PDAC is lacking. At present, additional clinical samples are being collected to further investigate the association between the expression of miR-139-5p or TMPO and the clinicopathological status of PDAC, and further data on the prognosis of miR-139-5p and TMPO in patients with PDAC will be presented. This preliminary study indicates a potential epigenetic therapy for PDAC.
Acknowledgements
Not applicable.
Funding
The study was supported by Renmin Hospital, Hubei University of Medicine (Hubei, China; grant no. N0161003).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
HT was mainly involved in experimental design and integral control. HZ and LZ performed the experiments, analyzed data and wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The present study was approved by the Human Ethics Review Committee of Renmin Hospital, Hubei University of Medicine. Informed consent was obtained from all patients.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
References
|
Sahakyan MA, Kim SC, Kleive D, Kazaryan AM, Song KB, Ignjatovic D, Buanes T, Røsok BI, Labori KJ and Edwin B: Laparoscopic distal pancreatectomy for pancreatic ductal adenocarcinoma: Long-term oncologic outcomes after standard resection. Surgery. 162:802–811. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Hwang CI, Boj SF, Clevers H and Tuveson DA: Preclinical models of pancreatic ductal adenocarcinoma. J Pathol. 238:197–204. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Dunne RF and Hezel AF: Genetics and biology of pancreatic ductal adenocarcinoma. Hematol Oncol Clin North Am. 29:595–608. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Siegel RL, Miller KD and Jemal A: Cancer statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM and Matrisian LM: Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74:2913–2921. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Moffitt RA, Marayati R, Flate EL, Volmar KE, Loeza SG, Hoadley KA, Rashid NU, Williams LA, Eaton SC, Chung AH, et al: Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet. 47:1168–1178. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Delpu Y, Hanoun N, Lulka H, Sicard F, Selves J, Buscail L, Torrisani J and Cordelier P: Genetic and epigenetic alterations in pancreatic carcinogenesis. Curr Genomics. 12:15–24. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Imaoka H, Toiyama Y, Okigami M, Yasuda H, Saigusa S, Ohi M, Tanaka K, Inoue Y, Mohri Y and Kusunoki M: Circulating microRNA-203 predicts metastases, early recurrence, and poor prognosis in human gastric cancer. Gastric Cancer. 19:744–753. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Acunzo M, Romano G, Wernicke D and Croce CM: MicroRNA and cancer-a brief overview. Adv Biol Regul. 57:1–9. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Catalanotto C, Cogoni C and Zardo G: MicroRNA in control of gene expression: An overview of nuclear functions. Int J Mol Sci. 17:E17122016. View Article : Google Scholar : PubMed/NCBI | |
|
Tüfekci KU, Meuwissen RL and Genç S: The role of microRNAs in biological processes. Methods Mol Biol. 1107:15–31. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang HD, Jiang LH, Sun DW, Li J and Tang JH: MiR-139-5p: Promising biomarker for cancer. Tumour Biol. 36:1355–1365. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Yonemori M, Seki N, Yoshino H, Matsushita R, Miyamoto K, Nakagawa M and Enokida H: Dual tumor-suppressors miR-139-5p and miR-139-3p targeting matrix metalloprotease 11 in bladder cancer. Cancer Sci. 107:1233–1242. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Sun C, Sang M, Li S, Sun X, Yang C, Xi Y, Wang L, Zhang F, Bi Y, Fu Y and Li D: Hsa-miR-139-5p inhibits proliferation and causes apoptosis associated with down-regulation of c-Met. Oncotarget. 6:39756–39792. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Hua S, Lei L, Deng L, Weng X, Liu C, Qi X, Wang S, Zhang D, Zou X, Cao C, et al: miR-139-5p inhibits aerobic glycolysis, cell proliferation, migration, and invasion in hepatocellular carcinoma via a reciprocal regulatory interaction with ETS1. Oncogene. 37:1624–1636. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Li Q, Liang X, Wang Y, Meng X, Xu Y, Cai S, Wang Z, Liu J and Cai G: miR-139-5p inhibits the epithelial-mesenchymal transition and enhances the chemotherapeutic sensitivity of colorectal cancer cells by downregulating BCL2. Sci Rep. 6:271572016. View Article : Google Scholar : PubMed/NCBI | |
|
Agosta C, Laugier J, Guyon L, Denis J, Bertherat J, Libé R, Boisson B, Sturm N, Feige JJ, Chabre O and Cherradi N: MiR-483-5p and miR-139-5p promote aggressiveness by targeting N-myc downstream-regulated gene family members in adrenocortical cancer. Int J Cancer. 143:944–957. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Li J, Su L, Gong YY, Ding ML, Hong SB, Yu S and Xiao HP: Downregulation of miR-139-5p contributes to the antiapoptotic effect of liraglutide on the diabetic rat pancreas and INS-1 cells by targeting IRS1. PLoS One. 12:e01735762017. View Article : Google Scholar : PubMed/NCBI | |
|
Marrero-Rodríguez D, Taniguchi-Ponciano K, Lopez-Sleman J, Romero-Morelos P, Mendoza-Rodríguez M, Garcia I, Huerta-Padilla V, Mantilla A, Duarte A, Piña P, et al: Thymopoietin beta and gamma isoforms as a potential diagnostic molecular marker for breast cancer: Preliminary data. Pathol Oncol Res. 21:1045–1050. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Gesson K, Vidak S and Foisner R: Lamina-associated polypeptide (LAP)2α and nucleoplasmic lamins in adult stem cell regulation and disease. Semin Cell Dev Biol. 29:116–124. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Dechat T, Vlcek S and Foisner R: Review: Lamina-associated polypeptide 2 isoforms and related proteins in cell cycle-dependent nuclear structure dynamics. J Struct Biol. 129:335–345. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang L, Wang G, Chen S, Ding J, Ju S, Cao H and Tian H: Depletion of thymopoietin inhibits proliferation and induces cell cycle arrest/apoptosis in glioblastoma cells. World J Surg Oncol. 14:2672016. View Article : Google Scholar : PubMed/NCBI | |
|
Kim HJ, Hwang SH, Han ME, Baek S, Sim HE, Yoon S, Baek SY, Kim BS, Kim JH, Kim SY and Oh SO: LAP2 is widely overexpressed in diverse digestive tract cancers and regulates motility of cancer cells. PLoS One. 7:e394822012. View Article : Google Scholar : PubMed/NCBI | |
|
Jung H, Lee HH, Song KY, Jeon HM and Park CH: Validation of the seventh edition of the American Joint Committee on Cancer TNM staging system for gastric cancer. Cancer. 117:2371–2378. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Ferreira HJ and Esteller M: Non-coding RNAs, epigenetics, and cancer: Tying it all together. Cancer Metastasis Rev. 37:55–73. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Yan H, Bonasio R, Simola DF, Liebig J, Berger SL and Reinberg D: DNA methylation in social insects: How epigenetics can control behavior and longevity. Annu Rev Entomol. 60:435–452. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Piletič K and Kunej T: MicroRNA epigenetic signatures in human disease. Arch Toxicol. 90:2405–2419. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Miyoshi J, Toden S, Yoshida K, Toiyama Y, Alberts SR, Kusunoki M, Sinicrope FA and Goel A: MiR-139-5p as a novel serum biomarker for recurrence and metastasis in colorectal cancer. Sci Rep. 7:433932017. View Article : Google Scholar : PubMed/NCBI | |
|
Furukawa K: LAP2 binding protein 1 (L2BP1/BAF) is a candidate mediator of LAP2-chromatin interaction. J Cell Sci. 112:2485–2492. 1999.PubMed/NCBI | |
|
Gant TM, Harris CA and Wilson KL: Roles of LAP2 proteins in nuclear assembly and DNA replication: Truncated LAP2beta proteins alter lamina assembly, envelope formation, nuclear size, and DNA replication efficiency in Xenopus laevis extracts. J Cell Biol. 144:1083–1096. 1999. View Article : Google Scholar : PubMed/NCBI | |
|
Dorner D, Vlcek S, Foeger N, Gajewski A, Makolm C, Gotzmann J, Hutchison CJ and Foisner R: Lamina-associated polypeptide 2alpha regulates cell cycle progression and differentiation via the retinoblastoma-E2F pathway. J Cell Biol. 173:83–93. 2006. View Article : Google Scholar : PubMed/NCBI |
