- Research
- Open access
- Published:
MiR-618 suppresses the proliferation, invasion, and migration of non-small lung cancer via the JAK2/STAT3 axis
Journal of Cardiothoracic Surgery volume 19, Article number: 679 (2024)
Abstract
Objective
The regulatory role of the miR-618/JAK2/STAT3 axis in non-small cell lung cancer cells (NSCLC) was investigated with the objective of identifying a target for the precise treatment of patients with NSCLC.
Methods
Initially, differential gene expression was identified in the GEO database, followed by a comprehensive bioinformatics analysis. The tissue and cell levels of miR-618 were assessed using qRT-PCR, while the protein levels of JAK2 and STAT3 were determined through western blotting analysis. The association between miR-618 and JAK2 was scrutinized through bioinformatics analysis and dual-luciferase experiments. To evaluate cell proliferation, migration, and invasion, MTT, wound-healing, and Transwell assays were employed.
Results
The expression of miR-618 is decreased in NSCLC, and it targets the JAK2/STAT3 pathway to inhibit the proliferation, invasion, and migration of NSCLC.
Conclusion
Our study demonstrates that a novel miR-618/JAK2/STAT3 signaling axis is involved in suppressing malignancy in NSCLC and provides a promising target for NSCLC therapy.
Introduction
Lung carcinoma is one of the leading causes of global cancer mortality.Based on the information from GLOBOCAN 2018 data, approximately 2.09Â million new cases and 1.76Â million deaths are reported each year [1]. Lung cancer ranks among the most prevalent malignant neoplasms in China. The 2015 data published by the National Cancer Center reveal that the 5-year prevalence rate of lung cancer in China during the period of 2006 to 2011 stood at 130.2 cases per 100,000 individuals.Of these cases, the prevalence rate for men was 84.6 (1/100 000), ranking second for malignant tumors, while the rate for women was 45.6 (1/100 000), ranking fourth for malignant tumors [2]. From a histopathological perspective, the two primary categories of lung carcinoma comprise small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC accounting for approximately 85% of all cases based on histological analysis [3]. While the treatment methods for lung cancer have become more diverse, the survival rate of lung cancer patients is still only about 15% with late-stage disease manifestations, histological heterogeneity of the tumor subtypes, and resistance to anti-tumor drugs being the key reasons for poor prognosis [4]. Understanding the underlying mechanisms of lung cancer tumorigenesis is essential in enhancing patient diagnosis, treatment, and prognosis.
The body of research indicates that non-coding RNAs (ncRNAs) are significantly involved in the development and advancement of non-small cell lung cancer (NSCLC) [5,6,7]. MicroRNAs (miRNAs), comprising small ncRNAs with a length of 20–24 nucleotides, have emerged as key players in this context [8, 9]. They were first discovered in 1993 in Caenorhabditis elegans [10, 11]. Since then, miRNAs have been shown to have significant importance in the regulatory pathways of both unicellular and multicellular eukaryotes. Small RNA molecules have the ability to selectively identify and attach to matching regions found in the 3’-untranslated portions (UTRs) of target messenger RNAs. This interaction can impede translation or induce degradation of the mRNA, ultimately causing post-transcriptional gene silencing [12]. In addition, miRNAs can also activate gene expression under certain conditions either directly or indirectly [13]. The miRBase database currently contains over 2500 mature miRNAs derived from 1188 miRNA precursors.
Thousands of miRNAs have been shown to be associated with various human diseases, including malignant tumors. In 2002, a study by Calin et al. showed a relationship between miRNA dysregulation and cancer [14]. In 2004, Takamizawa et al. demonstrated a relationship between miRNA expression and lung cancer [15]. miR-519d-3p has been found to inhibit the expression of Bcl-w and hypoxia-inducing factor (HIF)-1α, reducing hypoxia-induced tumorigenesis [16], while miR-487a-3p down-regulation inhibits the progression of NSCLC by targeting Smad7 [17].
Janus kinase 2 (JAK2) serves as a non-receptor tyrosine kinase signaling molecule responsible for transducing the effects of a range of hormones and cytokines such as interferon, erythropoietin, leptin, and growth hormone [18, 19]. JAK2 plays a critical role in the regulation of cellr volume, safeguarding cells during energy utilization and proliferation, and facilitating the survival of tumor cells. The JAK/STAT pathway is an evolutionarily conserved signaling pathway, involving many basic cell functions, such as cell growth and metastasis, which can lead to the development and progression of cancer [20].
The present study conducted differential analysis utilizing the GEO online database, revealing a significant downregulation of miR-618 expression in the peripheral blood of lung cancer patients compared to healthy individuals (Accession No. GSE24709) [21]. Subsequently, we conducted an analysis utilizing the Starbase database [22], which revealed a lower expression level of miR-618 in lung cancer tissues compared to normal lung tissues. Through the use of RT-qPCR validation on tissue samples, we observed a downregulation of miR-618 in NSCLC tissue cells. Our findings indicate that miR-618 specifically targets JAK2 within tumor cells, resulting in the suppression of migration and invasion in NSCLC cells by modulating the JAK2/STAT3 pathway, thus providing new insights into the pathogenesis of NSCLC.
Materials and methods
Human tissue specimens
Tissue samples (tumor and normal adjacent tissue) were obtained from lung cancer patients at the First Affiliated Hospital of Ningbo University. The specimens were procured from surgical excision of neoplasms, with the individuals having had no prior exposure to radiotherapy, chemotherapy, or targeted therapy prior to the operative procedure. Clinical information and case data were obtained from the patients at the time of surgery. All the patients provided written informed consent, and the research methodology was sanctioned by the Medical Ethics Committee of the First Affiliated Hospital of Ningbo University. Helsinki Declaration has been followed for involving human subjects in this study.
Cell culture
The cell lines utilized in the study were procured from the Chinese Academy of Sciences Cell Bank (CASCB, China), including one human normal bronchial epithelial cell line BEAS-2B and four human lung adenocarcinoma cell lines namely NCI-H1299,LTEP-A-2,SPC-A-1 and A549.BEAS-2B cells were cultured in DMEM medium (Hyclone, USA), while all human lung cancer cell lines were cultured in RPMI-1640 medium (Hyclone, USA). The cells mentioned above were all cultured in an environment containing 10% fetal bovine serum (PAN, Germany), and all cell lines were placed in a 5% CO2, 37 °C incubator (Thermo Fisher, USA).
Total RNA extraction and RT-qPCR
Total RNA was isolated from lung cancer tissues and cell lines employing the TRIzol reagent (Invitrogen, USA).mRNA was obtained by reverse-transcription of the total RNA using a reverse-transcription kit (Toyobo, Japan), and cDNA was synthesized from miRNA using a miRNA reverse-transcription kit (GenePharma, China). RT-qPCR was performed using SYBR Green 1 (Takara, Japan). β-actin and U6 were employed as internal reference standards, with the specific primers utilized detailed in Table S1 (additional file 1).
siRNAs, miRNA mimic, miRNA inhibitor, and transfection experiments
JAK2 siRNA, the miR-618 mimic and inhibitor, and a non-targeting negative control were purchased from GenePharma (Shanghai, China). Lipofectamine 2000 (Invitrogen, Germany) was used for transfection.After a span of forty-eight hours subsequent to transfection, the cellular entities were employed for the purpose of RNA extraction and identification through RT-qPCR. The transfected sequences of the miR-618 mimics and siRNA oligonucleotides are shown in Table S2, Additional file 1.
MTT assay
The transfected cells were seeded and cultured in 96-well plates for 12 h. Twenty microliters of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) solution were added to each well, after which the plate was incubated at 37˚C for 4 h. After removing the medium and MTT solution, 150 µl of DMSO was introduced, and the absorbance was measured using a microplate reader. (Bio-Rad, Hercules, CA, USA) every hour for 0, 24, 48, 72, and 96 h.
Colony formation assay
The transfected cells were evenly allocated into individual wells of 6-well plates, with each well containing a concentration of 500 cells. The plates underwent a 12-day incubation in a cell culture incubator, and then were subjected to three washes using phosphate-buffered saline (PBS). The colonies were then fixed with 4% paraformaldehyde for a duration of 30 min, followed by staining with 150 µl of 0.1% crystal violet(Solarbio, China) per well for a period of 15 min.
Transwell assay
A Transwell chamber with its upper and lower chambers separated by a polycarbonate microporous membrane (pore size 8 μm) and coated with artificial base glue was used. Cells were harvested and resuspended to a density of 1 × 106 cells/mL. One hundred microliters of this cell suspension were added to the upper chamber, and 500 µL of DMEM complete culture medium was added to the lower chamber. The Transwell chamber was then placed in a 37 °C, 5% CO2 incubator and cultured for 8 h. The polycarbonate microporous membrane was then removed from the chamber and the base, glue and cells on its upper surface were gently wiped with a cotton swab. The cells were fixed in neutral formaldehyde for 20 min, followed by staining with hematoxylin and eosin. Finally, the cells were examined under a microscope and the cells in five randomly selected fields of view were counted.
Wound-healing experiment
The transfected cells were distributed into a 6-well plate at a density of 2 × 105 cells per well, followed by an overnight incubation at 37 °C in a 5% CO2 environment. After ensuring that the cells were adherent, 2,4-diamino-4,6-dihydroxypyrimidine (DDP) was added for treatment, after which the cells were cultured until fully confluent. A linear scratch was made on the cell monolayer with a 200 µL sterile pipette tip and photomicrographs were taken immediately. After culturing for a further 48 h, the cells were again photographed and recorded. Image J software was used to measure the migration distance of each group of cells.
Western blotting
Total protein (including total, nuclear and cytoplasmic protein) was extracted from the cells using RIPA lysis buffer (50 mM Tris-HCl pH 8.0, 150 mM NaCl, 1%Triton X-100, and 1 protease inhibitor cocktail tablet/10 ml, Solarbio, Beijing, China) and quantified using a BCA protein assay kit (Beyotime, China). The Western blotting procedure was executed following established protocols. The primary antibodies were anti-JAK2 (Bioss Antibodies, Woburn, MA, USA), anti-STAT3 (Bioss), anti-p-STAT3 (Bioss), and anti-β-actin (Santa Cruz Biotechnology, Dallas, TX, USA).
Bioinformatic analysis
Starbase database was used to predict the difference in the expression of miR-618 between lung cancer tissues and normal tissues.
TargetScan software was used to predict the biological targets of miR-618 (TargetScanHuman 8.0).
Statistical analysis
Statistical analysis of the data was conducted using GraphPad Prism 8 software (GraphPad Software, La Jolla, CA, USA). Data were presented in the form of means ± standard deviations.The study was conducted with a minimum of three replications, with statistical significance determined at a p-value of less than 0.05. Photoshop CS6 software (Adobe Photoshop CS, Berkeley, CA, USA) was used for the statistical analysis of cell clone numbers, and quantitative analysis of the gray values of the Western blot bands was performed using Image J software.
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Results
Expression of miR-618 in NSCLC
Firstly, through online analysis of the GEO database, we observed a significant downregulation of miR-618 in the peripheral blood of lung cancer patients (Fig. 1A). The starbase database analysis revealed a notable downregulation of miR-618 within 512 lung cancer specimens in contrast to 20 control samples (Fig. 1B). We employed qRT-PCR to assess the expression of miR-618 in 50 sets of NSCLC tumors along with their neighboring non-cancerous tissues. The levels of miR-618 were notably reduced in the cancerous tissues in contrast to the neighboring non-cancerous tissues (Fig. 1C). Subsequent studies showed that the expression of miR-618 in NSCLC cells (LTEP-A-2, SPC-A-1, NCI-H1299, and A549) was significantly reduced compared with BEAS-2B cells (Fig. 1D). NSCLC cells were assessed to investigate the impact of miR-618 on their proliferation, migration, and invasion through gain and loss of function analyses. First, we designed and synthesized a miR-618 inhibitor, and observed that it could downregulate the expression of miR-618 by 48–63% (Fig. 1E). Furthermore, we employed miR-618 mimics for inducing ectopic expression of miR-618, observing a substantial up-regulation of miR-618 by 247-879-fold (Fig. 1F).
Expression of miR-618 in NSCLC. (A) Analysis conducted on the GEO database revealed a significant downregulation of miR-618 in the peripheral blood of lung cancer patients. (B) The starbase database predicts the expression level of miR-618 in 512 lung cancer tissue samples and 20 normal samples. (C) The differential expression of miR-618 was analyzed in 50 pairs of NSCLC tissues and corresponding noncancerous tissues. (D) qRT-PCR analysis of miR-618 expression in NSCLC cell lines. (E) The miR-618 expression levels were examined following the transfection of miR-NC and an miR-618 inhibitor in NCI-H1299 and LTEP-A-2 cells. (F) MiR-618 expression levels were analyzed post transfection of miR-NC and miR-618 mimics in NCI-H1299 and LTEP-A-2 cells. * P < 0.05, ** P < 0.01, *** P < 0.001
MiR-618 inhibits lung cancer cell proliferation, migration, and invasion
The results obtained from MTT and colony formation assays demonstrated that the downregulation of miR-618 significantly enhanced the growth and proliferation of LTEP-A-2 and NCI-H1299 cells. Conversely, upregulating miR-618 had the opposite impact on cell proliferation, suggesting that miR-618 suppressed the proliferation of NSCLC cells (Fig. 2A-B). Cellular scratching and invasion assays elucidated that suppression of miR-618 facilitated the migratory and invasive capacities of LTEP-A-2 and NCI-H1299 cells, whereas upregulation hindered cell migration and invasion (Fig. 2C-D).
MiR-618 inhibits lung cancer cell proliferation, migration, and invasion. (A) Proliferation of NCI-H1299 and LTEP-A-2 cells after overexpression or knockdown of miRNA-618, shown by MTT assays and (B) colony-forming assays; (C) Migration of miRNA-618-overexpressing or knockdown NCI-H1299 and LTEP-A-2 cells shown by wound-healing assays; (D) Invasion of miRNA-618-overexpressing or knockdown NCI-H1299 and LTEP-A-2 cells shown by Transwell assays. * P < 0.05, ** P < 0.01, *** P < 0.001
MiR-618 targets the JAK2 3’ UTR
The experimental investigations concerning cellular functions have indicated that miR-618 possesses the capability to impede the proliferation, invasion, and migration of NSCLC cells. We suspected that miR-618 might influence the progression of NSCLC via a distinct molecular mechanism. Research indicates that miRNAs have the ability to selectively attach to and control the activity of target genes in order to influence the advancement of NSCLC. TargetScan software predicted that miR-618 binds to JAK2 (Fig. 3A). To verify this prediction, we knocked down or overexpressed miR-618 in LTEP-A-2 and NCI-H1299 cells, confirming that JAK2 was regulated by miR-618 (Fig. 3B). For further exploration of this interaction, we conducted a dual-luciferase reporter assay. The findings indicated that after co-transfection of miR-618 mimics with JAK2 wild-type, the luciferase activity was significantly reduced, while co-transformation with the JAK2 mutant sequence had no effect (Fig. 3C). We conducted qRT-PCR on 50 pairs of NSCLC tissues and their corresponding non-cancerous tissues to examine the differential expression of JAK2. We observed a reduction in the expression of JAK2 in the tumor tissues of NSCLC patients compared to normal controls (Fig. 3D). The analysis of correlation reveals a decrease in the expression of miR-618 and an increase in the expression of JAK2 within lung cancer tissues, with their expressions demonstrating a negative correlation (r=-0.3242, p = 0.0202) (Fig. 3E). Finally, Western blotting showed that JAK2 knockdown significantly reduced the expression of both JAK2 and p-STAT3 protein, while the simultaneous knockdown of JAK2 and miR-618 restored the JAK2 and p-STAT3 protein levels.We further discovered that downregulating JAK2 leads to a decrease in the expression of CCND and c-MYC proteins, yet concomitant downregulation of JAK2 and miR-618 restores the levels of CCND and c-MYC proteins (Fig. 3F).
MiR-618 targets the JAK2 3’ UTR. (A) Prediction of interaction between miR-618 and the JAK2 3’ UTR the TargetScan database; (B) After overexpressing or knocking down miR-618, qPCR was used to detect expression of JAK2 in NCI-H1299 and LTEP-A-2 cells; (C) After transfection of NCI-H1299 and LTEP-A-2 cells with miR-618, the relative luciferase activity of the JAK2 3’ UTR wild-type or mutant luciferase vector was measured; (D) Differential expression analysis of JAK2 was conducted on 50 pairs of NSCLC tissues and their corresponding non-cancerous tissues. (E) Expression of miR-618 and JAK2 in lung cancer tissues was negatively correlated. (F) After overexpression or knockdown of miR-618, western blotting was used to detect expression of JAK2, STAT3, p-STAT3, CCND, and c-MYC in NCI-H1299 and LTEP-A-2 cells. * P < 0.05, ** P < 0.01, *** P < 0.001
Knockdown of JAK2 restores cell proliferation, migration, and invasion inhibited by miR-618 in NCI-H1299 and LTEP-A-2 cells
To confirm if miR-618 enhances lung cancer advancement through JAK2 regulation, we co-transfected the miR-618 inhibitor and JAK2 siRNA into LTEP-A-2 and NCI-H1299 cells. We designed MTT and clone formation assays to examine the effects of miR-618 and JAK2 on cells. The results showed that inhibiting JAK2 could inhibit cell proliferation, while inhibiting miR-618 could alleviate the inhibitory effect of JAK2 (Fig. 4A-B). Consistent with the above findings, it was found by wound-healing and transwell experiments that downregulation of miR-618 promoted cell migration and invasion that were inhibited by JAK2 knockdown (Fig. 4C-D).
Knockdown of JAK2 restores cell proliferation, migration, and invasion inhibited by miR-618 in NCI-H1299 and LTEP-A-2 cells. After co-transfection of the miR-618 inhibitor and si-JAK2, (A) MTT measurement of proliferation in cells; (B) Colony formation assay measurement of proliferation in cells; (C) Wound-healing assay measurement of migration in cells; (D) Transwell assay measurement of cell invasion. * P < 0.05, ** P < 0.01, *** P < 0.001
Discussion
MiRNAs, a subtype of small non-coding RNAs, have been extensively supported in the research literature regarding their involvement in tumor progression. Specifically, miR-618 has been identified to exert regulatory influences in various types of tumors. For example, MiR-618 has been observed to induce mesenchymal to epithelial transition (MET), and it inhibited prostate cancer migration and invasion by targeting FOXP2 and inhibiting TGF-β [23], and miR-618 has been identified to target the PI3K/Akt pathway to promote cell growth in human thyroid cancer, consequently leading to decelerated cellular proliferation and cell cycle arrest [24]. In this study, we demonstrated an association between miR-618 and lung cancer. MiR-618 expression was found to be notably decreased in lung cancer tissues, indicating a potential association between this decreased expression and the onset and progression of lung cancer. We further analyzed the specific molecular action of miR-618 in lung cancer. The findings from our experimental investigation indicated a decreased expression of miR-618 in cell lines associated with lung cancer. The findings from the MTT, clone formation, wound-healing, and Transwell assays collectively indicate that miR-618 exerts inhibitory effects on the proliferation, migration, and invasion capabilities of lung cancer cells. The findings align with the documented function of miR-618 in various malignancies. Overall, it can be inferred that miR-618 functions as a tumor suppressor in lung cancer. Dual-luciferase experiments showed that miR-618 targets the JAK2 3’-UTR directly.
JAK2, being part of the JAK family of protein tyrosine kinases, fulfills various functional roles in carcinogenesis [25]. Prior research has demonstrated that JAK2 functions as an oncogene through the modulation of STAT3 phosphorylation in human hepatocellular carcinoma, as well as in lung, colorectal, pancreatic, and gastric cancer [26,27,28]. The JAK/STAT pathway, a signaling pathway conserved throughout evolution, plays a role in cell growth and metastasis, contributing to its association with the initiation and progression of cancer [29]. JAK is phosphorylated and activated by itself, subsequently leading to the phosphorylation of STAT3. STAT3 then forms a homodimer and translocates to the nucleus, facilitating the transcription of multiple oncogenes such as c-MYC, Bcl-1, CCND, and Bcl-xL [30].
In various types of cancers, the MYC transcriptional network is dysregulated through multiple mechanisms, contributing to the initiation and maintenance of the disease [31]. CCND exhibits a high frequency of alterations in various tumors, playing a crucial role in controlling cell cycle progression and proliferation [32, 33]. Furthermore, we conducted a investigation into the downstream targets of the JAK/STAT pathway utilizing the Western blotting. We observed that the downregulation of JAK2 expression leads to a decrease in the levels of CCND and c-MYC proteins. Conversely, upon the downregulation of miR-618 along with JAK2, there is an elevation in the levels of CCND and c-MYC proteins. The research conducted revealed that miR-618 was observed to impede the autophosphorylation process of JAK2 through the targeting of the 3’utr of JAK2. This action subsequently led to the modulation of the JAK/STAT pathway, consequently influencing the downstream expression levels of c-MYC and CCND. These findings underscore the tumor suppressor function of miR-618 in NSCLC.
Currently, a variety of JAK2 inhibitors have entered clinical trials. Therefore, it is necessary to carry out related knockout and interference studies on lung cancer cell lines, which can further elucidate the regulatory role of the JAK/STAT pathway in NSCLC. Secondly, while we have explored the role of miR-618 and the JAK/STAT pathway in lung cancer in a variety of lung cancer cell lines, animal data are lacking. The construction of animal models would allow further verification and investigation of the miR-618 regulatory mechanism, and would also indicate the potential clinical benefit of JAK2 inhibitors in mouse lung cancer models.
Conclusions
In our research, we found that miR-618 significantly inhibits the growth, mobility, and invasion of lung cancer cells by targeting the JAK/STAT signaling pathway. These findings provide fresh insights into NSCLC development and may present pioneering strategies for NSCLC treatment.
Data availability
No datasets were generated or analysed during the current study.
References
Arbyn M, Weiderpass E, Bruni L, de Sanjosé S, Saraiya M, Ferlay J, Bray F. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. Lancet Global Health. 2020;8(2):e191–203.
Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. Cancer J Clin. 2016;66(2):115–32.
Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446–54.
Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clinic proceedings 2008, 83(5):584–594.
Goodall GJ, Wickramasinghe VO. RNA in cancer. Nat Rev Cancer. 2021;21(1):22–36.
Anastasiadou E, Jacob LS, Slack FJ. Non-coding RNA networks in cancer. Nat Rev Cancer. 2018;18(1):5–18.
Pan J, Meng X, Jiang N, Jin X, Zhou C, Xu D, Gong Z. Insights into the noncoding RNA-encoded peptides. Protein Pept Lett. 2018;25(8):720–7. https://doiorg.publicaciones.saludcastillayleon.es/10.2174/0929866525666180809142326.
Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discovery. 2017;16(3):203–22.
Yang C, Huang T, Liang Y et al. CTHRC1 targeted by miR-30a-5p regulates cell adhesion, invasion and migration in lung adenocarcinoma. J Cardiothorac Surg. 2022;17(1):46. Published 2022 Mar 21. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13019-022-01788-9
Lee RC, Feinbaum RL, Ambros V. The C. Elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75(5):843–54.
Bracken CP, Scott HS, Goodall GJ. A network-biology perspective of microRNA function and dysfunction in cancer. Nat Rev Genet. 2016;17(12):719–32.
Gebert LFR, MacRae IJ. Regulation of microRNA function in animals. Nat Rev Mol Cell Biol. 2019;20(1):21–37.
Cho WC. MicroRNAs: potential biomarkers for cancer diagnosis, prognosis and targets for therapy. Int J Biochem Cell Biol. 2010;42(8):1273–81.
Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 2002;99(24):15524–9.
Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 2004;64(11):3753–6.
Choi JY, Seok HJ, Kim RK, Choi MY, Lee SJ, Bae IH. miR-519d-3p suppresses tumorigenicity and metastasis by inhibiting Bcl-w and HIF-1α in NSCLC. Mol Therapy Oncolytics. 2021;22:368–79.
Fan Y, Hao J, Cen X, Song K, Yang C, Xiao S, Cheng S. Downregulation of miR-487a-3p suppresses the progression of non-small cell lung cancer via targeting Smad7. Drug development research 2021.
Perner F, Perner C, Ernst T, Heidel FH. Roles of JAK2 in aging, inflammation, Hematopoiesis and Malignant Transformation. Cells 2019, 8(8).
Nie S, Zhang L, Liu J, Wan Y, Jiang Y, Yang J, Sun R, Ma X, Sun G, Meng H, et al. ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer. J Experimental Clin cancer Research: CR. 2021;40(1):284.
Tian M, Qi Y, Zhang X, Wu Z, Chen J, Chen F, Guan W, Zhang S. Regulation of the JAK2-STAT5 pathway by Signaling molecules in the mammary gland. Front cell Dev Biology. 2020;8:604896.
Peripheral profiles from. Patients with cancerous and non cancerous lung diseases.Public on Mar 11, 2011.GSE24709,GEO Accession viewer (nih.gov).
Pan-Cancer Differential Expression. Analysis of microRNA genes across 32 types of cancers. 2021. https://rnasysu.com/encori/panMirDiffExp.php
Song XL, Tang Y, Lei XH, Zhao SC, Wu ZQ. miR-618 inhibits prostate Cancer Migration and Invasion by Targeting FOXP2. J Cancer. 2017;8(13):2501–10.
Yi L, Yuan Y. MicroRNA-618 modulates cell growth via targeting PI3K/Akt pathway in human thyroid carcinomas. Indian J Cancer. 2015;52(Suppl 3):E186–189.
Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Reviews Clin Oncol. 2018;15(4):234–48.
Wörmann SM, Song L, Ai J, Diakopoulos KN, Kurkowski MU, Görgülü K, Ruess D, Campbell A, Doglioni C, Jodrell D, et al. Loss of P53 function activates JAK2-STAT3 signaling to promote pancreatic tumor growth, stroma modification, and Gemcitabine Resistance in mice and is Associated with patient survival. Gastroenterology. 2016;151(1):180–e193112.
Neradugomma NK, Subramaniam D, Tawfik OW, Goffin V, Kumar TR, Jensen RA, Anant S. Prolactin signaling enhances colon cancer stemness by modulating notch signaling in a Jak2-STAT3/ERK manner. Carcinogenesis. 2014;35(4):795–806.
Wei C, Yang C, Wang S, Shi D, Zhang C, Lin X, Liu Q, Dou R, Xiong B. Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis. Mol Cancer. 2019;18(1):64.
Bose P, Verstovsek S. JAK2 inhibitors for myeloproliferative neoplasms: what is next? Blood. 2017;130(2):115–25.
Le-Trilling VTK, Wohlgemuth K, Rückborn MU, Jagnjic A, Maaßen F, Timmer L, Katschinski B. Trilling M. STAT2-Dependent Immune responses ensure host survival despite the Presence of a potent viral antagonist. J Virol 2018, 92(14).
Kalkat M, De Melo J, Hickman KA, Lourenco C, Redel C, Resetca D, Tamachi A, Tu WB, Penn LZ. MYC deregulation in primary human cancers. Genes (Basel). 2017;8(6):151.
Montalto FI, De Amicis F. Cyclin D1 in Cancer: a molecular connection for cell cycle control, Adhesion and Invasion in Tumor and Stroma. Cells. 2020;9(12):2648. Published 2020 Dec 9.
Qie S, Diehl JA. Cyclin D1, cancer progression, and opportunities in cancer treatment. J Mol Med (Berl). 2016;94(12):1313–26.
Acknowledgements
The authors thank their respective laboratory members and collaborators for critical review of this article. This work is supported by 2021 Ningbo Health Youth Backbone Talent Training Project (2021SWSONGG-ZCW), 2022 Medical New Talent Program(YTXXZCW-2023), Ningbo Public Welfare Technology Plan Project(2022S042), Zhejiang Medical and Health Program (2023KY1112) Ningbo Medical Science and Technology Program (2021Y14)Â and Wu Jieping Medical Foundation Project(320.6750.2022-22-43). The authors are thankful to patients who took part in this study.
Author information
Authors and Affiliations
Contributions
Mr. Ziyuan Chen is the first author of this paper. He co-designed and conducted the experiments and wrote the paper. Chen Wei collated the experimental data in Fig. 1. Zhiqi Hong collated the experimental data in Fig. 2. Wu Xianqiao and Fang Tianzheng jointly organized the experimental data in Fig. 4. ShengYuFei participated in the thesis writing. Fang Shuai experiment is designed. Mr. Chengwei Zhou is the corresponding author of this paper, and he supervised the writing of the paper. All authors reviewed the manuscript.
Corresponding authors
Ethics declarations
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Chen, Z., Chen, W., Hong, Z. et al. MiR-618 suppresses the proliferation, invasion, and migration of non-small lung cancer via the JAK2/STAT3 axis. J Cardiothorac Surg 19, 679 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13019-024-03160-5
Received:
Accepted:
Published:
DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13019-024-03160-5