Skip to main content
SpringerLink
Log in

Exploring the potential biological function of GRK2 in colorectal cancer

  • Original Article
  • Published:
Functional & Integrative Genomics Aims and scope Submit manuscript

Abstract

Background

Colorectal cancer (CRC) is a malignant tumor of the gastrointestinal tract with high morbidity and mortality. There is growing evidence that GRK2 plays a key role in the development and progression of several human cancers. However, the role and potential mechanisms of GRK2 in colon cancer (COAD) are unclear.

Methods

The expression data of GRK2 was downloaded from The Cancer Genome Atlas database (TCGA). Variation in GRK2 was explored based on the cBioPortal database. The TIMER and TISCH2 databases were used to analyse the relationship between GRK2 expression and tumor immune microenvironment (TME). A log-rank test was used to compare the prognosis of high and low expression of GRK2 groups. Detecting the effect of GRK2 on cell cycle and apoptosis induced by 5-Fluorouracil (5-FU) through the flow cytometry and detection of apoptosis-related molecules by Western blot.

Results

We demonstrated that GRK2 has a potential oncogenic role. GRK2 expression was upregulated in COAD, which predicted poorer overall survival in COAD patients. The cellular assays showed that GRK2 plays a role in the growth and proliferation of colon cancer cells, also the expression of GRK2 have relationship with the sensitivity of 5-FU and cell cycle progression.

Conclusions

Our results suggest that high GRK2 expression is closely associated with the development of tumor and affects the 5-FU sensitivity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Data availability

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding authors. All the data contained in the article are true and reliable. The original data of RNA-seq has been uploaded to NCBI’s SRA database, which can be queried according to the number PRJNA904417.

References

  • Benovic JL (2021) : Historical perspective of the G protein-coupled receptor kinase family. Cells 10(3)

  • Blondy S, David V, Verdier M, Mathonnet M, Perraud A, Christou N (2020) 5-Fluorouracil resistance mechanisms in colorectal cancer: from classical pathways to promising processes. Cancer Sci 111(9):3142–3154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E et al (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5):401–404

    Article  PubMed  Google Scholar 

  • Chen B, Khodadoust MS, Liu CL, Newman AM, Alizadeh AA (2018) : Profiling Tumor Infiltrating Immune Cells with CIBERSORT. Methods in molecular biology (Clifton, NJ) 1711:243–259

  • Concordet JP, Haeussler M (2018) CRISPOR: intuitive guide selection for CRISPR/Cas9 genome editing experiments and screens. Nucleic Acids Res 46(W1):W242–w245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Digre A, Lindskog C (2021) The human protein atlas-spatial localization of the human proteome in health and disease. Protein Science: Publication Protein Soc 30(1):218–233

    Article  CAS  Google Scholar 

  • Dinkel BA, Kremer KN, Rollins MR, Medlyn MJ, Hedin KE (2018) GRK2 mediates TCR-induced transactivation of CXCR4 and TCR-CXCR4 complex formation that drives PI3Kγ/PREX1 signaling and T cell cytokine secretion. J Biol Chem 293(36):14022–14039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fridman WH, Pagès F, Sautès-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12(4):298–306

    Article  CAS  PubMed  Google Scholar 

  • Fu X, Koller S, Abd Alla J, Quitterer U (2013) Inhibition of G-protein-coupled receptor kinase 2 (GRK2) triggers the growth-promoting mitogen-activated protein kinase (MAPK) pathway. J Biol Chem 288(11):7738–7755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gambardella J, Fiordelisi A, Santulli G, Ciccarelli M, Cerasuolo FA, Sala M, Sommella E, Campiglia P, Illario M, Iaccarino G et al (2020) : Exploiting GRK2 inhibition as a therapeutic option in Experimental Cancer Treatment: role of p53-Induced mitochondrial apoptosis. Cancers 12(12)

  • Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E et al (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6(269):pl1

    Article  PubMed  PubMed Central  Google Scholar 

  • Ge P, Wang W, Li L, Zhang G, Gao Z, Tang Z, Dang X, Wu Y (2019) Profiles of immune cell infiltration and immune-related genes in the tumor microenvironment of colorectal cancer. Biomed Pharmacotherapy = Biomedecine Pharmacotherapie 118:109228

    Article  CAS  Google Scholar 

  • Haraldsdottir S, Einarsdottir HM, Smaradottir A, Gunnlaugsson A, Halfdanarson TR (2014) [Colorectal cancer - review]. Laeknabladid 100(2):75–82

    PubMed  Google Scholar 

  • Ho J, Cocolakis E, Dumas VM, Posner BI, Laporte SA, Lebrun JJ (2005) The G protein-coupled receptor kinase-2 is a TGFbeta-inducible antagonist of TGFbeta signal transduction. EMBO J 24(18):3247–3258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ino Y, Yamazaki-Itoh R, Shimada K, Iwasaki M, Kosuge T, Kanai Y, Hiraoka N (2013) Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br J Cancer 108(4):914–923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lawes D, Taylor I (2005) Chemotherapy for colorectal cancer–an overview of current management for surgeons. Eur J Surg Oncology: J Eur Soc Surg Oncol Br Association Surg Oncol 31(9):932–941

    Article  CAS  Google Scholar 

  • Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, Li B, Liu XS (2017) TIMER: a web server for Comprehensive Analysis of Tumor-infiltrating Immune cells. Cancer Res 77(21):e108–e110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li T, Fu J, Zeng Z, Cohen D, Li J, Chen Q, Li B, Liu XS (2020) TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res 48(W1):W509–w514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P (2015) The Molecular signatures database (MSigDB) hallmark gene set collection. Cell Syst 1(6):417–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lokich J (1995) Infusional 5-FU for advanced colorectal cancer. J Infus Chemother 5(4):208–211

    CAS  PubMed  Google Scholar 

  • Longley DB, Harkin DP, Johnston PG (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3(5):330–338

    Article  CAS  PubMed  Google Scholar 

  • McQuade RM, Stojanovska V, Bornstein JC, Nurgali K (2017) Colorectal Cancer chemotherapy: the evolution of treatment and New approaches. Curr Med Chem 24(15):1537–1557

    Article  CAS  PubMed  Google Scholar 

  • Nakanishi Y, Diaz-Meco MT, Moscat J (2019) Serrated colorectal Cancer: the Road less travelled? Trends Cancer 5(11):742–754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nogués L, Reglero C, Rivas V, Salcedo A, Lafarga V, Neves M, Ramos P, Mendiola M, Berjón A, Stamatakis K et al (2016) G protein-coupled receptor kinase 2 (GRK2) promotes breast tumorigenesis through a HDAC6-Pin1 Axis. EBioMedicine 13:132–145

    Article  PubMed  PubMed Central  Google Scholar 

  • Pagès F, Mlecnik B, Marliot F, Bindea G, Ou FS, Bifulco C, Lugli A, Zlobec I, Rau TT, Berger MD et al (2018) International validation of the consensus immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet (London England) 391(10135):2128–2139

    Article  PubMed  Google Scholar 

  • Pathania AS, Ren X, Mahdi MY, Shackleford GM, Erdreich-Epstein A (2019) GRK2 promotes growth of medulloblastoma cells and protects them from chemotherapy-induced apoptosis. Sci Rep 9(1):13902

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  • Penela P, Rivas V, Salcedo A, Mayor F (2010a) Jr.: G protein-coupled receptor kinase 2 (GRK2) modulation and cell cycle progression. Proc Natl Acad Sci USA 107(3):1118–1123

    Article  ADS  CAS  PubMed  Google Scholar 

  • Penela P, Murga C, Ribas C, Lafarga V, Mayor F Jr. (2010b) The complex G protein-coupled receptor kinase 2 (GRK2) interactome unveils new physiopathological targets. Br J Pharmacol 160(4):821–832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prowatke I, Devens F, Benner A, Gröne EF, Mertens D, Gröne HJ, Lichter P, Joos S (2007) Expression analysis of imbalanced genes in prostate carcinoma using tissue microarrays. Br J Cancer 96(1):82–88

    Article  CAS  PubMed  Google Scholar 

  • Reglero C, Lafarga V, Rivas V, Albitre Á, Ramos P, Berciano SR, Tapia O, Martínez-Chantar ML, Mayor F Jr., Penela P (2020) : GRK2-Dependent HuR phosphorylation regulates HIF1α activation under Hypoxia or adrenergic stress. Cancers 12(5)

  • Rivas V, Nogués L, Reglero C, Mayor F Jr., Penela P (2014) Role of G protein-coupled receptor kinase 2 in tumoral angiogenesis. Mol Cell Oncol 1(4):e969166

    Article  PubMed  PubMed Central  Google Scholar 

  • Sethy C, Kundu CN (2021) 5-Fluorouracil (5-FU) resistance and the new strategy to enhance the sensitivity against cancer: implication of DNA repair inhibition. Biomed Pharmacotherapy = Biomedecine Pharmacotherapie 137:111285

    Article  CAS  PubMed  Google Scholar 

  • Subhan MA, Torchilin VP (2021) Neutrophils as an emerging therapeutic target and tool for cancer therapy. Life Sci 285:119952

    Article  CAS  PubMed  Google Scholar 

  • Sun D, Wang J, Han Y, Dong X, Ge J, Zheng R, Shi X, Wang B, Li Z, Ren P et al (2021) TISCH: a comprehensive web resource enabling interactive single-cell transcriptome visualization of tumor microenvironment. Nucleic Acids Res 49(D1):D1420–d1430

    Article  CAS  PubMed  Google Scholar 

  • The Genotype-Tissue (2013) Expression (GTEx) project. Nat Genet 45(6):580–585

    Article  Google Scholar 

  • Tian Y, Kharazmi E, Sundquist K, Sundquist J, Brenner H, Fallah M (2019) Familial colorectal cancer risk in half siblings and siblings: nationwide cohort study. BMJ (Clinical Res ed) 364:l803

    Google Scholar 

  • Tomczak K, Czerwińska P, Wiznerowicz M (2015) The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol (Poznan Poland) 19(1a):A68–77

    Google Scholar 

  • Vodenkova S, Buchler T, Cervena K, Veskrnova V, Vodicka P, Vymetalkova V (2020) 5-fluorouracil and other fluoropyrimidines in colorectal cancer: past, present and future. Pharmacol Ther 206:107447

    Article  CAS  PubMed  Google Scholar 

  • Wang HB, Yao H, Li CS, Liang LX, Zhang Y, Chen YX, Fang JY, Xu J (2017) Rise of PD-L1 expression during metastasis of colorectal cancer: implications for immunotherapy. J Dig Dis 18(10):574–581

    Article  CAS  PubMed  Google Scholar 

  • Waniczek D, Lorenc Z, Śnietura M, Wesecki M, Kopec A, Muc-Wierzgoń M (2017) Tumor-Associated Macrophages and Regulatory T Cells Infiltration and the clinical outcome in Colorectal Cancer. Arch Immunol Ther Exp 65(5):445–454

    Article  CAS  Google Scholar 

  • Wei Z, Hurtt R, Ciccarelli M, Koch WJ, Doria C (2012) Growth inhibition of human hepatocellular carcinoma cells by overexpression of G-protein-coupled receptor kinase 2. J Cell Physiol 227(6):2371–2377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei Z, Hurtt R, Gu T, Bodzin AS, Koch WJ, Doria C (2013) GRK2 negatively regulates IGF-1R signaling pathway and cyclins’ expression in HepG2 cells. J Cell Physiol 228(9):1897–1901

    Article  CAS  PubMed  Google Scholar 

  • Yuan H, Yan M, Zhang G, Liu W, Deng C, Liao G, Xu L, Luo T, Yan H, Long Z et al (2019) CancerSEA: a cancer single-cell state atlas. Nucleic Acids Res 47(D1):D900–d908

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Yu X, Zheng L, Zhang Y, Li Y, Fang Q, Gao R, Kang B, Zhang Q, Huang JY et al (2018a) Lineage tracking reveals dynamic relationships of T cells in colorectal cancer. Nature 564(7735):268–272

    Article  ADS  CAS  PubMed  Google Scholar 

  • Zhang H, Liu H, Shen Z, Lin C, Wang X, Qin J, Qin X, Xu J, Sun Y (2018b) Tumor-infiltrating neutrophils is prognostic and predictive for postoperative adjuvant Chemotherapy Benefit in patients with gastric Cancer. Ann Surg 267(2):311–318

    Article  PubMed  Google Scholar 

  • Zhou L, Wang MY, Liang ZY, Zhou WX, You L, Pan BJ, Liao Q, Zhao YP (2016) G-protein-coupled receptor kinase 2 in pancreatic cancer: clinicopathologic and prognostic significance. Hum Pathol 56:171–177

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Fundamental Research Funds for the Basic Ability Improvement Project for Young and Middle-Aged Teachers in Guangxi Colleges and Universities (Grant No. 2022KY0532), Youjiang Medical University for Nationalities Scientific Research Project (Grant No. yy2020ky039), and the Scientific Research and Technology Development Plan of Baise (Grant No. 20212347).Guangxi Natural Science Foundation (2023GXNSFAA140064).

Author information

Authors and Affiliations

  1. Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, 430072, China

    Meng Gao, Xinyi Liang, Mengqi Fan, Yutong Wu & Run-Lei Du

  2. Reproductive Medicine, Guangxi Medical and health key discipline construction project of the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, 533000, China

    Ming-you Dong

Authors
  1. Meng Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xinyi Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mengqi Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yutong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ming-you Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Run-Lei Du
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Meng Gao and Xinyi Liang conceived and designed the study. Mingyou Dong searched for data and wrote programming code. Meng Gao was involved in the writing of the manuscript. Yutong Wu collected pictures and graphs as well as edited them. Mengqi Fan was responsible for the collection and assembly of data, data analysis. Runlei Du provided help in revising the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

Corresponding authors

Correspondence to Ming-you Dong or Run-Lei Du.

Ethics declarations

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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.

Supplementary Material 1

Supplementary Material 2

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gao, M., Liang, X., Fan, M. et al. Exploring the potential biological function of GRK2 in colorectal cancer. Funct Integr Genomics 24, 51 (2024). https://doi.org/10.1007/s10142-024-01322-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10142-024-01322-1

Keywords

Search

Navigation