DOCK4 is a Novel Prognostic Biomarker and Correlated with Immune Infiltrates in Colon Adenocarcinoma


Cite item

Full Text

Abstract

Background:Dedicator for cytokinesis 4 (DOCK4) is a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1. However, the functions of DOCK4 concerning the tumor microenvironment (TME) in colon adenocarcinoma (COAD) remain uncertain.

Methods:The TIMER and GEPIA databases were used to analyze the DOCK4 expression between COAD tissues and adjunct normal tissues. The PrognoScan database was used to assess the prognosis of DOCK4 expression in COAD. The co-expression networks of DOCK4 in COAD were constructed by the LinkedOmics website. Furthermore, the correlation between DOCK4 expression and TME of COAD was explored using TIMER and TISIDB databases. Finally, the clone formation assay was used to further verify the function of DOCK4 in COAD. The Western blotting assay was used to confirm the mechanism related to DOCK4 in COAD.

Results:The DOCK4 expression was different significantly in COAD tissues and paracancerous tissues. The DOCK4 was found to play a poor role in the prognosis of patients with COAD. The DOCK4 was found to participate in the TME by promoting immune evasion of COAD. The reduction of DOCK4 expression inhibited the clone formation and Ras-associated protein 1A (Rap1A) expression of HCT116 cells.

Conclusions:DOCK4 potentially plays an important role in the regulation of TME in COAD. DOCK4 facilitates the development through the Rap1A pathway, thus becoming a novel prognostic biomarker in COAD.

About the authors

Xingjiang Xie

Department of General Surgery, Wenjiang District People’s Hospital of Chengdu

Author for correspondence.
Email: info@benthamscience.net

Yi Lu

Department of Otorhinolaryngology, Suining Central Hospital

Email: info@benthamscience.net

Bo Wang

Department of General Surgery, Wenjiang District People’s Hospital of Chengdu

Email: info@benthamscience.net

Xiaobin Yin

Department of General Surgery, Wenjiang District People’s Hospital of Chengdu

Email: info@benthamscience.net

Jianfeng Chen

Department of General Surgery, Wenjiang District People’s Hospital of Chengdu

Email: info@benthamscience.net

References

  1. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin., 2019, 69(1), 7-34. doi: 10.3322/caac.21551 PMID: 30620402
  2. Garborg, K.; Holme, Ø.; Løberg, M.; Kalager, M.; Adami, H.O.; Bretthauer, M. Current status of screening for colorectal cancer. Ann. Oncol., 2013, 24(8), 1963-1972. doi: 10.1093/annonc/mdt157 PMID: 23619033
  3. Edwards, B.K.; Ward, E.; Kohler, B.A.; Eheman, C.; Zauber, A.G.; Anderson, R.N.; Jemal, A.; Schymura, M.J.; Lansdorp-Vogelaar, I.; Seeff, L.C.; van Ballegooijen, M.; Goede, S.L.; Ries, L.A.G. Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer, 2010, 116(3), 544-573. doi: 10.1002/cncr.24760 PMID: 19998273
  4. Calon, A.; Espinet, E.; Palomo-Ponce, S.; Tauriello, D.V.F.; Iglesias, M.; Céspedes, M.V.; Sevillano, M.; Nadal, C.; Jung, P.; Zhang, X.H.F.; Byrom, D.; Riera, A.; Rossell, D.; Mangues, R.; Massagué, J.; Sancho, E.; Batlle, E. Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell, 2012, 22(5), 571-584. doi: 10.1016/j.ccr.2012.08.013 PMID: 23153532
  5. Picard, E.; Verschoor, C.P.; Ma, G.W.; Pawelec, G. Relationships between immune landscapes, genetic subtypes and responses to immunotherapy in colorectal cancer. Front. Immunol., 2020, 11, 369. doi: 10.3389/fimmu.2020.00369 PMID: 32210966
  6. Cao, H.; Xu, E.; Liu, H.; Wan, L.; Lai, M. Epithelial–mesenchymal transition in colorectal cancer metastasis: A system review. Pathol. Res. Pract., 2015, 211(8), 557-569. doi: 10.1016/j.prp.2015.05.010 PMID: 26092594
  7. Dou, R.; Liu, K.; Yang, C.; Zheng, J.; Shi, D.; Lin, X.; Wei, C.; Zhang, C.; Fang, Y.; Huang, S.; Song, J.; Wang, S.; Xiong, B. EMT‐cancer cells‐derived exosomal miR‐27b‐3p promotes circulating tumour cells‐mediated metastasis by modulating vascular permeability in colorectal cancer. Clin. Transl. Med., 2021, 11(12), e595. doi: 10.1002/ctm2.595 PMID: 34936736
  8. Wang, H.; Liu, J.; Li, J.; Zang, D.; Wang, X.; Chen, Y.; Gu, T.; Su, W.; Song, N. Identification of gene modules and hub genes in colon adenocarcinoma associated with pathological stage based on WGCNA analysis. Cancer Genet., 2020, 242, 1-7. doi: 10.1016/j.cancergen.2020.01.052 PMID: 32036224
  9. Jiang, X.; Wang, J.; Deng, X.; Xiong, F.; Ge, J.; Xiang, B.; Wu, X.; Ma, J.; Zhou, M.; Li, X.; Li, Y.; Li, G.; Xiong, W.; Guo, C.; Zeng, Z. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol. Cancer, 2019, 18(1), 10. doi: 10.1186/s12943-018-0928-4 PMID: 30646912
  10. Quail, D.F.; Joyce, J.A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med., 2013, 19(11), 1423-1437. doi: 10.1038/nm.3394 PMID: 24202395
  11. Maker, A.V. Precise identification of immunotherapeutic targets for solid malignancies using clues within the tumor microenvironment—Evidence to turn on the LIGHT. OncoImmunology, 2016, 5(1), e1069937. doi: 10.1080/2162402X.2015.1069937 PMID: 26942091
  12. Qiu, C.; Shi, W.; Wu, H.; Zou, S.; Li, J.; Wang, D.; Liu, G.; Song, Z.; Xu, X.; Hu, J.; Geng, H. Identification of molecular subtypes and a prognostic signature based on inflammation-related genes in colon adenocarcinoma. Front. Immunol., 2021, 12, 769685. doi: 10.3389/fimmu.2021.769685 PMID: 35003085
  13. Katz, S.C.; Bamboat, Z.M.; Maker, A.V.; Shia, J.; Pillarisetty, V.G.; Yopp, A.C.; Hedvat, C.V.; Gonen, M.; Jarnagin, W.R.; Fong, Y.; D’Angelica, M.I.; DeMatteo, R.P. Regulatory T cell infiltration predicts outcome following resection of colorectal cancer liver metastases. Ann. Surg. Oncol., 2013, 20(3), 946-955. doi: 10.1245/s10434-012-2668-9 PMID: 23010736
  14. Maker, A.V.; Ito, H.; Mo, Q.; Weisenberg, E.; Qin, L.X.; Turcotte, S.; Maithel, S.; Shia, J.; Blumgart, L.; Fong, Y.; Jarnagin, W.R.; DeMatteo, R.P.; D’Angelica, M.I. Genetic evidence that intratumoral T-cell proliferation and activation are associated with recurrence and survival in patients with resected colorectal liver metastases. Cancer Immunol. Res., 2015, 3(4), 380-388. doi: 10.1158/2326-6066.CIR-14-0212 PMID: 25600439
  15. Lazarus, J.; Maj, T.; Smith, J.J.; Perusina Lanfranca, M.; Rao, A.; D’Angelica, M.I.; Delrosario, L.; Girgis, A.; Schukow, C.; Shia, J.; Kryczek, I.; Shi, J.; Wasserman, I.; Crawford, H.; Nathan, H.; Pasca Di Magliano, M.; Zou, W.; Frankel, T.L. Spatial and phenotypic immune profiling of metastatic colon cancer. JCI Insight, 2018, 3(22), e121932. doi: 10.1172/jci.insight.121932 PMID: 30429368
  16. Yajnik, V.; Paulding, C.; Sordella, R.; McClatchey, A.I.; Saito, M.; Wahrer, D.C.R.; Reynolds, P.; Bell, D.W.; Lake, R.; van den Heuvel, S.; Settleman, J.; Haber, D.A. DOCK4, a GTPase activator, is disrupted during tumorigenesis. Cell, 2003, 112(5), 673-684. doi: 10.1016/S0092-8674(03)00155-7 PMID: 12628187
  17. Mei, Y.; Li, K.; Zhang, Z.; Li, M.; Yang, H.; Wang, H.; Huang, X.; Li, X.; Shi, S.; Yang, H. miR-33b-3p acts as a tumor suppressor by targeting DOCK4 in prostate cancer. Front. Oncol., 2021, 11, 740452. doi: 10.3389/fonc.2021.740452 PMID: 34804930
  18. Debruyne, D.N.; Turchi, L.; Burel-Vandenbos, F.; Fareh, M.; Almairac, F.; Virolle, V.; Figarella-Branger, D.; Baeza-Kallee, N.; Lagadec, P.; kubiniek, V.; Paquis, P.; Fontaine, D.; Junier, M-P.; Chneiweiss, H.; Virolle, T. DOCK4 promotes loss of proliferation in glioblastoma progenitor cells through nuclear beta-catenin accumulation and subsequent miR-302-367 cluster expression. Oncogene, 2018, 37(2), 241-254. doi: 10.1038/onc.2017.323 PMID: 28925399
  19. Aladowicz, E.; Granieri, L.; Marocchi, F.; Punzi, S.; Giardina, G.; Ferrucci, P.F.; Mazzarol, G.; Capra, M.; Viale, G.; Confalonieri, S.; Gandini, S.; Lotti, F.; Lanfrancone, L.; Shc, D. ShcD binds DOCK4, promotes ameboid motility and metastasis dissemination, predicting poor prognosis in melanoma. Cancers (Basel), 2020, 12(11), 3366. doi: 10.3390/cancers12113366 PMID: 33202906
  20. Zhao, Q.; Zhong, J.; Lu, P.; Feng, X.; Han, Y.; Ling, C.; Guo, W.; Zhou, W.; Yu, F.; Li, J. DOCK4 is a platinum-chemosensitive and prognostic-related biomarker in ovarian cancer. PPAR Res., 2021, 2021, 1-12. doi: 10.1155/2021/6629842 PMID: 33613670
  21. Li, T.; Fan, J.; Wang, B.; Traugh, N.; Chen, Q.; Liu, J.S.; Li, B.; Liu, X.S. TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res., 2017, 77(21), e108-e110. doi: 10.1158/0008-5472.CAN-17-0307 PMID: 29092952
  22. Tang, Z.; Li, C.; Kang, B.; Gao, G.; Li, C.; Zhang, Z. GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res., 2017, 45(W1), W98-W102. doi: 10.1093/nar/gkx247 PMID: 28407145
  23. Mizuno, H.; Kitada, K.; Nakai, K.; Sarai, A. PrognoScan: A new database for meta-analysis of the prognostic value of genes. BMC Med. Genomics, 2009, 2(1), 18. doi: 10.1186/1755-8794-2-18 PMID: 19393097
  24. Vasaikar, S.V.; Straub, P.; Wang, J.; Zhang, B. LinkedOmics: Analyzing multi-omics data within and across 32 cancer types. Nucleic Acids Res., 2018, 46(D1), D956-D963. doi: 10.1093/nar/gkx1090 PMID: 29136207
  25. Ru, B.; Wong, C.N.; Tong, Y.; Zhong, J.Y.; Zhong, S.S.W.; Wu, W.C.; Chu, K.C.; Wong, C.Y.; Lau, C.Y.; Chen, I.; Chan, N.W.; Zhang, J.; Wren, J. TISIDB: An integrated repository portal for tumor–immune system interactions. Bioinformatics, 2019, 35(20), 4200-4202. doi: 10.1093/bioinformatics/btz210 PMID: 30903160
  26. Wu, Y.; Zhou, J.; Li, Y.; Zhou, Y.; Cui, Y.; Yang, G.; Hong, Y. Rap1A Regulates Osteoblastic Differentiation via the ERK and p38 Mediated Signaling. PLoS One, 2015, 10(11), e0143777. doi: 10.1371/journal.pone.0143777 PMID: 26599016
  27. Haggar, F.; Boushey, R. Colorectal cancer epidemiology: Incidence, mortality, survival, and risk factors. Clin. Colon Rectal Surg., 2009, 22(4), 191-197. doi: 10.1055/s-0029-1242458 PMID: 21037809
  28. O’Connell, J.B.; Maggard, M.A.; Ko, C.Y. Colon cancer survival rates with the new American joint committee on Cancer J Natl Cancer Inst., 2004, 96(19), 1420-1425.
  29. Mahajan, U.M.; Langhoff, E.; Goni, E.; Costello, E.; Greenhalf, W.; Halloran, C.; Ormanns, S.; Kruger, S.; Boeck, S.; Ribback, S.; Beyer, G.; Dombroswki, F.; Weiss, F.U.; Neoptolemos, J.P.; Werner, J.; D’Haese, J.G.; Bazhin, A.; Peterhansl, J.; Pichlmeier, S.; Büchler, M.W.; Kleeff, J.; Ganeh, P.; Sendler, M.; Palmer, D.H.; Kohlmann, T.; Rad, R.; Regel, I.; Lerch, M.M.; Mayerle, J. Immune cell and stromal signature associated with progression-free survival of patients with resected pancreatic ductal adenocarcinoma. Gastroenterology, 2018, 155(5), 1625-1639.e2. doi: 10.1053/j.gastro.2018.08.009 PMID: 30092175
  30. Bilotta, M.T.; Antignani, A.; Fitzgerald, D.J. Managing the TME to improve the efficacy of cancer therapy. Front. Immunol., 2022, 13, 954992. doi: 10.3389/fimmu.2022.954992 PMID: 36341428
  31. Singh, P.P.; Sharma, P.K.; Krishnan, G.; Lockhart, A.C. Immune checkpoints and immunotherapy for colorectal cancer. Gastroenterol. Rep. (Oxf.), 2015, 3(4), gov053. doi: 10.1093/gastro/gov053 PMID: 26510455
  32. Kalyan, A.; Kircher, S.; Shah, H.; Mulcahy, M.; Benson, A. Updates on immunotherapy for colorectal cancer. J. Gastrointest. Oncol., 2018, 9(1), 160-169. doi: 10.21037/jgo.2018.01.17 PMID: 29564182
  33. Glaire, M.A.; Ryan, N.A.J.; Ijsselsteijn, M.E.; Kedzierska, K.; Obolenski, S.; Ali, R.; Crosbie, E.J.; Bosse, T.; Miranda, N.F.C.C.; Church, D.N. Discordant prognosis of mismatch repair deficiency in colorectal and endometrial cancer reflects variation in antitumour immune response and immune escape. J. Pathol., 2022, 257(3), 340-351. doi: 10.1002/path.5894 PMID: 35262923
  34. Kunimura, K.; Uruno, T.; Fukui, Y. DOCK family proteins: Key players in immune surveillance mechanisms. Int. Immunol., 2020, 32(1), 5-15. doi: 10.1093/intimm/dxz067 PMID: 31630188
  35. Ge, W.; Cai, W.; Bai, R.; Hu, W.; Wu, D.; Zheng, S.; Hu, H. A novel 4-gene prognostic signature for hypermutated colorectal cancer. Cancer Manag. Res., 2019, 11, 1985-1996. doi: 10.2147/CMAR.S190963 PMID: 30881123
  36. Yu, J.; Wu, W.K.K.; Li, X.; He, J.; Li, X.X.; Ng, S.S.M.; Yu, C.; Gao, Z.; Yang, J.; Li, M.; Wang, Q.; Liang, Q.; Pan, Y.; Tong, J.H.; To, K.F.; Wong, N.; Zhang, N.; Chen, J.; Lu, Y.; Lai, P.B.S.; Chan, F.K.L.; Li, Y.; Kung, H.F.; Yang, H.; Wang, J.; Sung, J.J.Y. Novel recurrently mutated genes and a prognostic mutation signature in colorectal cancer. Gut, 2015, 64(4), 636-645. doi: 10.1136/gutjnl-2013-306620 PMID: 24951259
  37. Yu, J.R.; Tai, Y.; Jin, Y.; Hammell, M.C.; Wilkinson, J.E.; Roe, J.S.; Vakoc, C.R.; Van Aelst, L. TGF-β/Smad signaling through DOCK4 facilitates lung adenocarcinoma metastasis. Genes Dev., 2015, 29(3), 250-261. doi: 10.1101/gad.248963.114 PMID: 25644601
  38. Westbrook, J.A.; Wood, S.L.; Cairns, D.A.; McMahon, K.; Gahlaut, R.; Thygesen, H.; Shires, M.; Roberts, S.; Marshall, H.; Oliva, M.R.; Dunning, M.J.; Hanby, A.M.; Selby, P.J.; Speirs, V.; Mavria, G.; Coleman, R.E.; Brown, J.E. Identification and validation of DOCK4 as a potential biomarker for risk of bone metastasis development in patients with early breast cancer. J. Pathol., 2019, 247(3), 381-391. doi: 10.1002/path.5197 PMID: 30426503
  39. Hiramoto, K.; Negishi, M.; Katoh, H. Dock4 is regulated by RhoG and promotes Rac-dependent cell migration. Exp. Cell Res., 2006, 312(20), 4205-4216. doi: 10.1016/j.yexcr.2006.09.006 PMID: 17027967
  40. Wang, Y.Y.; Yan, L.; Yang, S.; Xu, H.N.; Chen, T.T.; Dong, Z.Y.; Chen, S.L.; Wang, W.R.; Yang, Q.L.; Chen, C.J. Long noncoding RNA AC073284.4 suppresses epithelial–mesenchymal transition by sponging miR‐18b‐5p in paclitaxel‐resistant breast cancer cells. J. Cell. Physiol., 2019, 234(12), 23202-23215. doi: 10.1002/jcp.28887 PMID: 31215650
  41. Steidl, C.; Lee, T.; Shah, S.P.; Farinha, P.; Han, G.; Nayar, T.; Delaney, A.; Jones, S.J.; Iqbal, J.; Weisenburger, D.D.; Bast, M.A.; Rosenwald, A.; Muller-Hermelink, H.K.; Rimsza, L.M.; Campo, E.; Delabie, J.; Braziel, R.M.; Cook, J.R.; Tubbs, R.R.; Jaffe, E.S.; Lenz, G.; Connors, J.M.; Staudt, L.M.; Chan, W.C.; Gascoyne, R.D. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N. Engl. J. Med., 2010, 362(10), 875-885. doi: 10.1056/NEJMoa0905680 PMID: 20220182
  42. Nishikawa, H.; Sakaguchi, S. Regulatory T cells in cancer immunotherapy. Curr. Opin. Immunol., 2014, 27, 1-7. doi: 10.1016/j.coi.2013.12.005 PMID: 24413387
  43. Koelzer, V.H.; Canonica, K.; Dawson, H.; Sokol, L.; Karamitopoulou-Diamantis, E.; Lugli, A.; Zlobec, I. Phenotyping of tumor-associated macrophages in colorectal cancer: Impact on single cell invasion (tumor budding) and clinicopathological outcome. OncoImmunology, 2016, 5(4), e1106677. doi: 10.1080/2162402X.2015.1106677 PMID: 27141391
  44. Sinicrope, F.A.; Rego, R.L.; Ansell, S.M.; Knutson, K.L.; Foster, N.R.; Sargent, D.J. Intraepithelial effector (CD3+)/regulatory (FoxP3+) T-cell ratio predicts a clinical outcome of human colon carcinoma. Gastroenterology, 2009, 137(4), 1270-1279. doi: 10.1053/j.gastro.2009.06.053 PMID: 19577568
  45. Fiegle, E.; Doleschel, D.; Koletnik, S.; Rix, A.; Weiskirchen, R.; Borkham-Kamphorst, E.; Kiessling, F.; Lederle, W. Dual CTLA-4 and PD-L1 blockade inhibits tumor growth and liver metastasis in a highly aggressive orthotopic mouse model of colon cancer. Neoplasia, 2019, 21(9), 932-944. doi: 10.1016/j.neo.2019.07.006 PMID: 31412307
  46. van Willigen, W.W.; Bloemendal, M.; Gerritsen, W.R.; Schreibelt, G.; de Vries, I.J.M.; Bol, K.F. Dendritic cell cancer therapy: Vaccinating the right patient at the right time. Front. Immunol., 2018, 9, 2265. doi: 10.3389/fimmu.2018.02265 PMID: 30327656
  47. Llosa, N.J.; Cruise, M.; Tam, A.; Wicks, E.C.; Hechenbleikner, E.M.; Taube, J.M.; Blosser, R.L.; Fan, H.; Wang, H.; Luber, B.S.; Zhang, M.; Papadopoulos, N.; Kinzler, K.W.; Vogelstein, B.; Sears, C.L.; Anders, R.A.; Pardoll, D.M.; Housseau, F. The vigorous immune micro-environment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov., 2015, 5(1), 43-51. doi: 10.1158/2159-8290.CD-14-0863 PMID: 25358689
  48. Azimi, F.; Scolyer, R.A.; Rumcheva, P.; Moncrieff, M.; Murali, R.; McCarthy, S.W.; Saw, R.P.; Thompson, J.F. Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J. Clin. Oncol., 2012, 30(21), 2678-2683. doi: 10.1200/JCO.2011.37.8539 PMID: 22711850
  49. Hattori, M.; Minato, N. Rap1 GTPase: Functions, regulation, and malignancy. J. Biochem., 2003, 134(4), 479-484. doi: 10.1093/jb/mvg180 PMID: 14607972
  50. Crosas-Molist, E.; Samain, R.; Kohlhammer, L.; Orgaz, J.L.; George, S.L.; Maiques, O.; Barcelo, J.; Sanz-Moreno, V. Rho GTPase signaling in cancer progression and dissemination. Physiol. Rev., 2022, 102(1), 455-510. doi: 10.1152/physrev.00045.2020 PMID: 34541899
  51. Huang, M.; Liang, C.; Li, S.; Zhang, J.; Guo, D.; Zhao, B.; Liu, Y.; Peng, Y.; Xu, J.; Liu, W.; Guo, G.; Shi, L. Two Autism/Dyslexia Linked Variations of DOCK4 Disrupt the Gene Function on Rac1/Rap1 Activation, Neurite Outgrowth, and Synapse Development. Front. Cell. Neurosci., 2020, 13, 577. doi: 10.3389/fncel.2019.00577 PMID: 32009906

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers