LTB4R Promotes the Occurrence and Progression of Clear Cell Renal Cell Carcinoma (ccRCC) by Regulating the AKT/mTOR Signaling Pathway
Abstract
:1. Introduction
2. Materials and Methods
2.1. ccRCC Cohort Collection and Preprocessing
2.2. Cell Recovery and Culture
2.3. Plasmid and siRNA Transfection
2.4. RNA Extraction and Real-Time Quantitative PCR Detection (qRT-PCR)
2.5. CCK8 Assays
2.6. Colony Formation Assays
2.7. Transwell Experiment
2.8. Flow Cytometry for Apoptosis and Cell Cycle
2.9. Western Blotting
2.10. Statistical Analysis
3. Results
3.1. LTB4R Expression and Its Effect on Survival and Clinical Stages in ccRCC
3.2. Interfering with LTB4R Inhibited the Proliferation and Clone Formation of Renal Cancer Cells In Vitro
3.3. LTB4R Knockdown Promoted Apoptosis and Inhibited Cell Cycle Progression in ccRCC Cells
3.4. LTB4R Knockdown Suppressed Migration, Invasion, and Epithelial-Mesenchymal Transformation (EMT)
3.5. LTB4R Promoted the Proliferation and Clone Formation of ccRCC Cells
3.6. LTB4R Suppressed Apoptosis and Promoted Cell Cycle Progression in ccRCC Cells
3.7. LTB4R Promoted Migration, Invasion, and Epithelial–Mesenchymal Transformation (EMT)
3.8. LTB4R Expression Was Related to Apoptosis, Cell Cycle, and EMT
3.9. LTB4R Regulation of the AKT/mTOR Signaling Pathway
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Wettersten, H.I.; Abu Aboud, O.; Lara, P.N., Jr.; Weiss, R.H. Metabolic reprogramming in clear cell renal cell carcinoma. Nat. Rev. Nephrol. 2017, 13, 410–419. [Google Scholar] [CrossRef]
- Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2022. CA Cancer J. Clin. 2022, 72, 7–33. [Google Scholar] [CrossRef] [PubMed]
- Wang, K.; Sun, Y.; Tao, W.; Fei, X.; Chang, C. Androgen receptor (AR) promotes clear cell renal cell carcinoma (ccRCC) migration and invasion via altering the circHIAT1/miR-195-5p/29a-3p/29c-3p/CDC42 signals. Cancer Lett. 2017, 394, 1–12. [Google Scholar] [CrossRef]
- Cerbone, L.; Cattrini, C.; Vallome, G.; Latocca, M.M.; Boccardo, F.; Zanardi, E. Combination therapy in metastatic renal cell carcinoma: Back to the future? Semin. Oncol. 2020, 47, 361–366. [Google Scholar] [CrossRef] [PubMed]
- Braun, D.A.; Bakouny, Z.; Hirsch, L.; Flippot, R.; Van Allen, E.M.; Wu, C.J.; Choueiri, T.K. Beyond conventional immune-checkpoint inhibition—Novel immunotherapies for renal cell carcinoma. Nat. Rev. Clin. Oncol. 2021, 18, 199–214. [Google Scholar] [CrossRef]
- Johdi, N.A.; Sukor, N.F. Colorectal Cancer Immunotherapy: Options and Strategies. Front. Immunol. 2020, 11, 1624. [Google Scholar] [CrossRef]
- Hegde, P.S.; Chen, D.S. Top 10 Challenges in Cancer Immunotherapy. Immunity 2020, 52, 17–35. [Google Scholar] [CrossRef] [PubMed]
- Xu, Z.; Zeng, S.; Gong, Z.; Yan, Y. Exosome-based immunotherapy: A promising approach for cancer treatment. Mol. Cancer 2020, 19, 160. [Google Scholar] [CrossRef]
- Linehan, W.M.; Ricketts, C.J. The Cancer Genome Atlas of renal cell carcinoma: Findings and clinical implications. Nat. Rev. Urol. 2019, 16, 539–552. [Google Scholar] [CrossRef]
- Ghatalia, P.; Gordetsky, J.; Kuo, F.; Dulaimi, E.; Cai, K.Q.; Devarajan, K.; Bae, S.; Naik, G.; Chan, T.A.; Uzzo, R.; et al. Prognostic impact of immune gene expression signature and tumor infiltrating immune cells in localized clear cell renal cell carcinoma. J. Immunother. Cancer 2019, 7, 139. [Google Scholar] [CrossRef]
- Yokomizo, T.; Nakamura, M.; Shimizu, T. Leukotriene receptors as potential therapeutic targets. J. Clin. Investig. 2018, 128, 2691–2701. [Google Scholar] [CrossRef]
- Wu, H.-H.; Yan, X.; Chen, Z.; Du, G.-W.; Bai, X.-J.; Tuoheti, K.; Liu, T.-Z. GNRH1 and LTB4R might be novel immune-related prognostic biomarkers in clear cell renal cell carcinoma (ccRCC). Cancer Cell Int. 2021, 21, 354. [Google Scholar] [CrossRef] [PubMed]
- Wang, N.; He, X.; Zhao, J.; Jiang, H.; Cheng, X.; Xia, Y.; Xu, H.E.; He, Y. Structural basis of leukotriene B4 receptor 1 activation. Nat. Commun. 2022, 13, 1156. [Google Scholar] [CrossRef] [PubMed]
- Jala, V.R.; Bodduluri, H.; Satpathy, S.R.; Chheda, Z.; Sharma, R.K.; Haribabu, B. The yin and yang of leukotriene B4 mediated inflammation in cancer. Semin. Immunol. 2017, 33, 58–64. [Google Scholar] [CrossRef] [PubMed]
- Kim, H.; Choi, J.-A.; Park, G.-S.; Kim, J.-H. BLT2 up-regulates interleukin-8 production and promotes the invasiveness of breast cancer cells. PLoS ONE 2012, 7, e49186. [Google Scholar] [CrossRef]
- Lv, J.; Xiong, Y.; Li, W.; Yang, W.; Zhao, L.; He, R. BLT1 Mediates Bleomycin-Induced Lung Fibrosis Independently of Neutrophils and CD4+ T Cells. J. Immunol. 2017, 198, 1673–1684. [Google Scholar] [CrossRef] [Green Version]
- Alzahrani, A.S. PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside. Semin. Cancer Biol. 2019, 59, 125–132. [Google Scholar] [CrossRef]
- Shorning, B.Y.; Dass, M.S.; Smalley, M.J.; Pearson, H.B. The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling. Int. J. Mol. Sci. 2020, 21, 4507. [Google Scholar] [CrossRef]
- Liang, M.; Lv, J.; Jiang, Z.; He, H.; Chen, C.; Xiong, Y.; Zhu, X.; Xue, Y.; Yu, Y.; Yang, S.; et al. Promotion of Myofibroblast Differentiation and Tissue Fibrosis by the Leukotriene B4 -Leukotriene B4 Receptor Axis in Systemic Sclerosis. Arthritis Rheumatol. 2020, 72, 1013–1025. [Google Scholar] [CrossRef]
- Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008, 455, 1061–1068. [Google Scholar] [CrossRef]
- Edgar, R.; Domrachev, M.; Lash, A.E. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002, 30, 207–210. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lonsdale, J.; Thomas, J.; Salvatore, M.; Phillips, R.; Lo, E.; Shad, S.; Hasz, R.; Walters, G.; Garcia, F.; Young, N.; et al. The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 2013, 45, 580–585. [Google Scholar] [CrossRef]
- Giannelli, G.; Koudelkova, P.; Dituri, F.; Mikulits, W. Role of epithelial to mesenchymal transition in hepatocellular carcinoma. J. Hepatol. 2016, 65, 798–808. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lamouille, S.; Xu, J.; Derynck, R. Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 2014, 15, 178–196. [Google Scholar] [CrossRef] [Green Version]
- Li, M.; Fu, W.; Wo, L.; Shu, X.; Liu, F.; Li, C. miR-128 and its target genes in tumorigenesis and metastasis. Exp. Cell Res. 2013, 319, 3059–3064. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hanzelmann, S.; Castelo, R.; Guinney, J. GSVA: Gene set variation analysis for microarray and RNA-seq data. BMC Bioinform. 2013, 14, 7. [Google Scholar] [CrossRef] [Green Version]
- Krishna, C.; DiNatale, R.G.; Kuo, F.; Srivastava, R.M.; Vuong, L.; Chowell, D.; Gupta, S.; Vanderbilt, C.; Purohit, T.A.; Liu, M.; et al. Single-cell sequencing links multiregional immune landscapes and tissue-resident T cells in ccRCC to tumor topology and therapy efficacy. Cancer Cell 2021, 39, 662–677.e6. [Google Scholar] [CrossRef]
- Reinartz, S.; Finkernagel, F.; Adhikary, T.; Rohnalter, V.; Schumann, T.; Schober, Y.; Nockher, W.A.; Nist, A.; Stiewe, T.; Jansen, J.M.; et al. A transcriptome-based global map of signaling pathways in the ovarian cancer microenvironment associated with clinical outcome. Genome Biol. 2016, 17, 108. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tong, W.G.; Ding, X.-Z.; Hennig, R.; Witt, R.C.; Standop, J.; Pour, P.M.; Adrian, T.E. Leukotriene B4 receptor antagonist LY293111 inhibits proliferation and induces apoptosis in human pancreatic cancer cells. Clin. Cancer Res. 2002, 8, 3232–3242. [Google Scholar]
- Motzer, R.J.; Penkov, K.; Haanen, J. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2019, 380, 1103–1115. [Google Scholar] [CrossRef]
- Rini, B.I.; Plimack, E.R.; Stus, V. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2019, 380, 1116–1127. [Google Scholar] [CrossRef]
- Kooshapur, H.; Choudhury, N.R.; Simon, B.; Mühlbauer, M.; Jussupow, A.; Fernandez, N.; Jones, A.N.; Dallmann, A.; Gabel, F.; Camilloni, C.; et al. Structural basis for terminal loop recognition and stimulation of pri-miRNA-18a processing by hnRNP A1. Nat. Commun. 2018, 9, 2479. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhou, H.; Xu, R.Z.; Gu, Y.; Shi, P.F.; Qian, S. Targeting of phospho-eIF4E by homoharringtonine eradicates a distinct subset of human acute myeloid leukemia. Leuk. Lymphoma 2020, 61, 1084–1096. [Google Scholar] [CrossRef] [PubMed]
- Zhao, S.; Yao, K.; Liu, K.; Huang, L.; Jiang, Y.; Li, J.; Dong, Z.; Dong, Z. Bestatin Cream Impairs Solar Simulated LightDriven Skin Inflammation and Skin Carcinogenesis in Mice. J. Investig. Dermatol. 2021, 141, 2699–2709.e2. [Google Scholar] [CrossRef] [PubMed]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Zhang, X.; Wu, H.; Yan, X.; Ma, J.; Chen, Z. LTB4R Promotes the Occurrence and Progression of Clear Cell Renal Cell Carcinoma (ccRCC) by Regulating the AKT/mTOR Signaling Pathway. Cells 2022, 11, 3606. https://doi.org/10.3390/cells11223606
Zhang X, Wu H, Yan X, Ma J, Chen Z. LTB4R Promotes the Occurrence and Progression of Clear Cell Renal Cell Carcinoma (ccRCC) by Regulating the AKT/mTOR Signaling Pathway. Cells. 2022; 11(22):3606. https://doi.org/10.3390/cells11223606
Chicago/Turabian StyleZhang, Xiao, Huahui Wu, Xin Yan, Jiajun Ma, and Zhao Chen. 2022. "LTB4R Promotes the Occurrence and Progression of Clear Cell Renal Cell Carcinoma (ccRCC) by Regulating the AKT/mTOR Signaling Pathway" Cells 11, no. 22: 3606. https://doi.org/10.3390/cells11223606
APA StyleZhang, X., Wu, H., Yan, X., Ma, J., & Chen, Z. (2022). LTB4R Promotes the Occurrence and Progression of Clear Cell Renal Cell Carcinoma (ccRCC) by Regulating the AKT/mTOR Signaling Pathway. Cells, 11(22), 3606. https://doi.org/10.3390/cells11223606