DPP2/7 is a Potential Predictor of Prognosis and Target in Immunotherapy in Colorectal Cancer: An Integrative Multi-omics Analysis


Cite item

Full Text

Abstract

Background::Colorectal cancer (CRC) ranks among the leading causes of cancerrelated deaths.

Objective::This study aimed to illuminate the relationship between DPP7 (also known as DPP2) and CRC through a combination of bioinformatics and experimental methodologies.

Methods::A multi-dimensional bioinformatic analysis on DPP7 was executed, covering its expression, survival implications, clinical associations, functional roles, immune interactions, and drug sensitivities. Experimental validations involved siRNA-mediated DPP7 knockdown and various cellular assays.

Results::Data from the Cancer Genome Atlas (TCGA) identified high DPP7 expression in solid CRC tumors, with elevated levels adversely affecting patient prognosis. A shift from the N0 to the N2 stage in CRC was associated with increased DPP7 expression. Functional insights indicated the involvement of DPP7 in cancer progression, particularly in extracellular matrix disassembly. Immunological analyses showed its association with immunosuppressive entities, and in vitro experiments in CRC cell lines underscored its oncogenic attributes.

Conclusion::DPP7 could serve as a CRC prognosis marker, functioning as an oncogene and representing a potential immunotherapeutic target.

About the authors

Zhihao Shang

The First School of Clinical Medicine, Nanjing University of Chinese Medicine

Email: info@benthamscience.net

Yueyang Lai

The First School of Clinical Medicine, Nanjing University of Chinese Medicine

Author for correspondence.
Email: info@benthamscience.net

Haibo Cheng

The First School of Clinical Medicine., Nanjing University of Chinese Medicine

Author for correspondence.
Email: info@benthamscience.net

References

  1. Ye, W.; Ling, S.; Liu, R.Y.; Pan, Z.Z.; Wang, G.; Gao, S.; Wu, J.; Cao, L.; Dong, L.; Li, Y.; Zhou, Y.; Du, W.; Meng, X.; Chen, J.; Guan, X.; He, Y.; Pan, C.; Zheng, X.F.S.; Lu, X.; Chen, S.; Huang, W. Exome sequencing reveals the genetic landscape and frequent inactivation of PCDHB3 in Chinese rectal cancers. J. Pathol., 2018, 245(2), 222-234. doi: 10.1002/path.5073 PMID: 29537081
  2. Wiig, J.N.; Poulsen, J.P.; Tveit, K.M.; Olsen, D.R.; Giercksky, K.E. Intra-operative irradiation (IORT) for primary advanced and recurrent rectal cancer. Eur. J. Cancer, 2000, 36(7), 868-874. doi: 10.1016/S0959-8049(00)00015-0 PMID: 10785591
  3. He, C.; Duan, X.; Guo, N.; Chan, C.; Poon, C.; Weichselbaum, R.R.; Lin, W. Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint blockade cancer immunotherapy. Nat. Commun., 2016, 7(1), 12499. doi: 10.1038/ncomms12499 PMID: 27530650
  4. Waumans, Y.; Baerts, L.; Kehoe, K.; Lambeir, A.M.; De Meester, I. The dipeptidyl peptidase family, prolyl oligopeptidase, and prolyl carboxypeptidase in the immune system and inflammatory disease, including atherosclerosis. Front. Immunol., 2015, 6, 387. doi: 10.3389/fimmu.2015.00387 PMID: 26300881
  5. Ng, L.; Foo, D.C.C.; Wong, C.K.H.; Man, A.T.K.; Lo, O.S.H.; Law, W.L. Repurposing DPP-4 inhibitors for colorectal cancer: A retrospective and single center study. Cancers, 2021, 13(14), 3588. doi: 10.3390/cancers13143588 PMID: 34298800
  6. Shah, C.; Hong, Y.R.; Bishnoi, R.; Ali, A.; Skelton, W.P., IV; Dang, L.H.; Huo, J.; Dang, N.H. Impact of DPP4 inhibitors in survival of patients with prostate, pancreas, and breast cancer. Front. Oncol., 2020, 10, 405. doi: 10.3389/fonc.2020.00405 PMID: 32296640
  7. da Silva, B.R.; Laird, M.E.; Yatim, N.; Fiette, L.; Ingersoll, M.A.; Albert, M.L. Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy. Nat. Immunol., 2015, 16(8), 850-858. doi: 10.1038/ni.3201
  8. Huang, J.; Liu, X.; Wei, Y.; Li, X.; Gao, S.; Dong, L.; Rao, X.; Zhong, J. Emerging role of dipeptidyl peptidase-4 in autoimmune disease. Front. Immunol., 2022, 13, 830863. doi: 10.3389/fimmu.2022.830863 PMID: 35309368
  9. Klemann, C.; Wagner, L.; Stephan, M.; von Hörsten, S. Cut to the chase: A review of CD26/dipeptidyl peptidase-4's (DPP4) entanglement in the immune system. Clin. Exp. Immunol., 2016, 185(1), 1-21. doi: 10.1111/cei.12781 PMID: 26919392
  10. Ohnuma, K.; Hatano, R.; Morimoto, C. DPP4 in anti-tumor immunity: Going beyond the enzyme. Nat. Immunol., 2015, 16(8), 791-792. doi: 10.1038/ni.3210 PMID: 26194276
  11. Wagner, L.; Klemann, C.; Stephan, M.; von Hörsten, S. Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins. Clin. Exp. Immunol., 2016, 184(3), 265-283. doi: 10.1111/cei.12757 PMID: 26671446
  12. Zhao, Y.; Yang, L.; Wang, X.; Zhou, Z. The New insights from DPP‐4 inhibitors: Their potential immune modulatory function in autoimmune diabetes. Diabetes Metab. Res. Rev., 2014, 30(8), 646-653. doi: 10.1002/dmrr.2530 PMID: 24446278
  13. Maes, M.B.; Scharpé, S.; De Meester, I. Dipeptidyl peptidase II (DPPII), a review. Clin. Chim. Acta, 2007, 380(1-2), 31-49. doi: 10.1016/j.cca.2007.01.024 PMID: 17328877
  14. Danilov, A.V.; Danilova, O.V.; Brown, J.R.; Rabinowitz, A.; Klein, A.K.; Huber, B.T. Dipeptidyl peptidase 2 apoptosis assay determines the B-cell activation stage and predicts prognosis in chronic lymphocytic leukemia. Exp. Hematol., 2010, 38(12), 1167-1177. doi: 10.1016/j.exphem.2010.08.008 PMID: 20817072
  15. Chiravuri, M.; Schmitz, T.; Yardley, K.; Underwood, R.; Dayal, Y.; Huber, B.T. A novel apoptotic pathway in quiescent lymphocytes identified by inhibition of a post-proline cleaving aminodipeptidase: A candidate target protease, quiescent cell proline dipeptidase. J. Immunol., 1999, 163(6), 3092-3099. doi: 10.4049/jimmunol.163.6.3092 PMID: 10477574
  16. Mele, D.A.; Sampson, J.F.; Huber, B.T. Th17 differentiation is the default program for DPP2‐deficient T‐cell differentiation. Eur. J. Immunol., 2011, 41(6), 1583-1593. doi: 10.1002/eji.201041157 PMID: 21469121
  17. Zeng, T.; Zhou, Y.; Yu, Y.; Wang, J.; Wu, Y.; Wang, X.; Zhu, L.; Zhou, L.; Wan, L. rmMANF prevents sepsis-associated lung injury via inhibiting endoplasmic reticulum stress-induced ferroptosis in mice. Int. Immunopharmacol., 2023, 114, 109608. doi: 10.1016/j.intimp.2022.109608 PMID: 36700778
  18. Zhang, Z.; Gao, J.; Yu, J.; Zhang, N.; Fu, Y.; Jiang, X.; Wang, X.; Song, J.; Wen, Z. Transcriptome analysis of novel macrophage M1-related biomarkers and potential therapeutic agents in ischemia-reperfusion injury after lung transplantation based on the WGCNA and CIBERSORT algorithms. Transpl. Immunol., 2023, 79, 101860. doi: 10.1016/j.trim.2023.101860 PMID: 37230395
  19. Yin, S.; Li, W.; Wang, J.; Wu, H.; Hu, J.; Feng, Y. Screening of key genes associated with m6A methylation in diabetic nephropathy patients by CIBERSORT and weighted gene coexpression network analysis. Am. J. Transl. Res., 2022, 14(4), 2280-2290. PMID: 35559414
  20. Geeleher, P.; Cox, N.; Huang, R.S. pRRophetic: An R package for prediction of clinical chemotherapeutic response from tumor gene expression levels. PLoS One, 2014, 9(9), e107468. doi: 10.1371/journal.pone.0107468 PMID: 25229481
  21. Zhao, P.; Zhen, H.; Zhao, H.; Huang, Y.; Cao, B. Identification of hub genes and potential molecular mechanisms related to radiotherapy sensitivity in rectal cancer based on multiple datasets. J. Transl. Med., 2023, 21(1), 176. doi: 10.1186/s12967-023-04029-2 PMID: 36879254
  22. Cheng, B.; Tang, C.; Xie, J.; Zhou, Q.; Luo, T.; Wang, Q.; Huang, H. Cuproptosis illustrates tumor micro-environment features and predicts prostate cancer therapeutic sensitivity and prognosis. Life Sci., 2023, 325, 121659. doi: 10.1016/j.lfs.2023.121659 PMID: 37011878
  23. Arora, M.; Kumari, S.; Singh, J.; Chopra, A.; Chauhan, S.S. PAXX, Not NHEJ1 is an independent prognosticator in colon cancer. Front. Mol. Biosci., 2020, 7, 584053. doi: 10.3389/fmolb.2020.584053 PMID: 33195430
  24. Bishara, L.A.; Machour, F.E.; Awwad, S.W.; Ayoub, N. NELF complex fosters BRCA1 and RAD51 recruitment to DNA damage sites and modulates sensitivity to PARP inhibition. DNA Repair, 2021, 97, 103025. doi: 10.1016/j.dnarep.2020.103025 PMID: 33248388
  25. Lv, S.; Zhao, X.; Zhang, E.; Yan, Y.; Ma, X.; Li, N.; Zou, Q.; Sun, L.; Song, T. Lysine demethylase KDM1A promotes cell growth via FKBP8–BCL2 axis in hepatocellular carcinoma. J. Biol. Chem., 2022, 298(9), 102374. doi: 10.1016/j.jbc.2022.102374 PMID: 35970393
  26. Ma, W.; Yang, L.; Liu, H.; Chen, P.; Ren, H.; Ren, P. PAXX is a novel target to overcome resistance to doxorubicin and cisplatin in osteosarcoma. Biochem. Biophys. Res. Commun., 2020, 521(1), 204-211. doi: 10.1016/j.bbrc.2019.10.108 PMID: 31640855
  27. van Vlierberghe, P.; Meijerink, J.P.P.; Lee, C.; Ferrando, A.A.; Look, A.T.; van Wering, E.R.; Beverloo, H.B.; Aster, J.C.; Pieters, R. A new recurrent 9q34 duplication in pediatric T-cell acute lymphoblastic leukemia. Leukemia, 2006, 20(7), 1245-1253. doi: 10.1038/sj.leu.2404247 PMID: 16673019
  28. Yeo, M.S.; Subhash, V.V.; Suda, K.; Balcıoğlu, H.E.; Zhou, S.; Thuya, W.L.; Loh, X.Y.; Jammula, S.; Peethala, P.C.; Tan, S.H.; Xie, C.; Wong, F.Y.; Ladoux, B.; Ito, Y.; Yang, H.; Goh, B.C.; Wang, L.; Yong, W.P. FBXW5 promotes tumorigenesis and metastasis in gastric cancer via activation of the FAK-Src signaling pathway. Cancers, 2019, 11(6), 836. doi: 10.3390/cancers11060836 PMID: 31213005
  29. Dhanasekaran, R.; Deutzmann, A.; Fernandez, M.W.D.; Hansen, A.S.; Gouw, A.M.; Felsher, D.W. The MYC oncogene — the grand orchestrator of cancer growth and immune evasion. Nat. Rev. Clin. Oncol., 2022, 19(1), 23-36. doi: 10.1038/s41571-021-00549-2 PMID: 34508258
  30. Han, Y.; Liu, D.; Li, L. PD-1/PD-L1 pathway: Current researches in cancer. Am. J. Cancer Res., 2020, 10(3), 727-742. PMID: 32266087
  31. Stulc, T.; Sedo, A. Inhibition of multifunctional dipeptidyl peptidase-IV: Is there a risk of oncological and immunological adverse effects? Diabetes Res. Clin. Pract., 2010, 88(2), 125-131. doi: 10.1016/j.diabres.2010.02.017 PMID: 20303610
  32. Yu, D.M.T.; Yao, T.W.; Chowdhury, S.; Nadvi, N.A.; Osborne, B.; Church, W.B.; McCaughan, G.W.; Gorrell, M.D. The dipeptidyl peptidase IV family in cancer and cell biology. FEBS J., 2010, 277(5), 1126-1144. doi: 10.1111/j.1742-4658.2009.07526.x PMID: 20074209
  33. Mentlein, R.; Struckhoff, G. Purification of two dipeptidyl aminopeptidases II from rat brain and their action on proline-containing neuropeptides. J. Neurochem., 1989, 52(4), 1284-1293. doi: 10.1111/j.1471-4159.1989.tb01877.x PMID: 2564425
  34. Mallela, J.; Yang, J.; Shariat-Madar, Z. Prolylcarboxypeptidase: A cardioprotective enzyme. Int. J. Biochem. Cell Biol., 2009, 41(3), 477-481. doi: 10.1016/j.biocel.2008.02.022 PMID: 18396440
  35. a) Talbot, P.; Dicarlantonio, G. Cytochemical localization of dipeptidyl peptidase II (DPP-II) in mature guinea pig sperm. J. Histochem. Cytochem., 1985, 33(11), 1169-1172.; b) Maes, B.; Lambeir, A.M.; Van der Veken, P.; De Winter, B.; Augustyns, K.; Scharpe, S.; Meester, I. De;, In vivo effects of a potent, selective DPPII inhibitor: UAMC00039 is a possible tool for the elucidation of the physiological function of DPPII. Adv. Exp. Med. Biol., 2006, 575, 73-85.; c) Maes, B.; Lambeir, A.M.; Van der Veken, P.; De Winter, B.; Augustyns, K.; Scharpe, S.; Meester, I. De Kinetic investigation of human dipeptidyl peptidase II (DPPII)-mediated hydrolysis of dipeptide derivatives and its identification as quiescent cell proline dipeptidase (QPP)/dipeptidyl peptidase 7 (DPP7). Biochem. J., 2005, 386(pt 2), 315-324.
  36. Aguilera, M.O.; Robledo, E.; Melani, M.; Wappner, P.; Colombo, M.I. FKBP8 is a novel molecule that participates in the regulation of the autophagic pathway. Biochim. Biophys. Acta Mol. Cell Res., 2022, 1869(5), 119212. doi: 10.1016/j.bbamcr.2022.119212 PMID: 35090967
  37. Hu, J.; Zacharek, S.; He, Y.J.; Lee, H.; Shumway, S.; Duronio, R.J.; Xiong, Y. WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by DDB1–CUL4–ROC1 ligase. Genes Dev., 2008, 22(7), 866-871. doi: 10.1101/gad.1624008 PMID: 18381890
  38. Yao, Y.; Liu, Z.; Huang, S.; Huang, C.; Cao, Y.; Li, L.; Guo, H.; Liu, F.; Huang, S.; Liao, Q.; He, X.; Chen, J.; Li, J.; Xiang, X.; Xiong, J.; Deng, J. The E3 ubiquitin ligase, FBXW5, promotes the migration and invasion of gastric cancer through the dysregulation of the Hippo pathway. Cell Death Discov., 2022, 8(1), 79. doi: 10.1038/s41420-022-00868-y PMID: 35210431
  39. Hui, X.; Hu, F.; Liu, J.; Li, C.; Yang, Y.; Shu, S.; Liu, P.; Wang, F.; Li, S. FBXW5 acts as a negative regulator of pathological cardiac hypertrophy by decreasing the TAK1 signaling to pro-hypertrophic members of the MAPK signaling pathway. J. Mol. Cell. Cardiol., 2021, 151, 31-43. doi: 10.1016/j.yjmcc.2020.09.008 PMID: 32971071
  40. Ohue, Y.; Nishikawa, H. Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? Cancer Sci., 2019, 110(7), 2080-2089. doi: 10.1111/cas.14069 PMID: 31102428
  41. Masuda, K.; Kornberg, A.; Miller, J.; Lin, S.; Suek, N.; Botella, T.; Secener, K.A.; Bacarella, A.M.; Cheng, L.; Ingham, M.; Rosario, V.; Al-Mazrou, A.M.; Lee-Kong, S.A.; Kiran, R.P.; Stoeckius, M.; Smibert, P.; Del Portillo, A.; Oberstein, P.E.; Sims, P.A.; Yan, K.S.; Han, A. Multiplexed single-cell analysis reveals prognostic and nonprognostic T cell types in human colorectal cancer. JCI Insight, 2022, 7(7), e154646. doi: 10.1172/jci.insight.154646 PMID: 35192548
  42. Cheung, K.J.J.; Johnson, N.A.; Affleck, J.G.; Severson, T.; Steidl, C.; Ben-Neriah, S.; Schein, J.; Morin, R.D.; Moore, R.; Shah, S.P.; Qian, H.; Paul, J.E.; Telenius, A.; Relander, T.; Lam, W.; Savage, K.; Connors, J.M.; Brown, C.; Marra, M.A.; Gascoyne, R.D.; Horsman, D.E. Acquired TNFRSF14 mutations in follicular lymphoma are associated with worse prognosis. Cancer Res., 2010, 70(22), 9166-9174. doi: 10.1158/0008-5472.CAN-10-2460 PMID: 20884631
  43. Li, Y.; Chen, Y.; Miao, L.; Wang, Y.; Yu, M.; Yan, X.; Zhao, Q.; Cai, H.; Xiao, Y.; Huang, G. Stress-induced upregulation of TNFSF4 in cancer-associated fibroblast facilitates chemoresistance of lung adenocarcinoma through inhibiting apoptosis of tumor cells. Cancer Lett., 2021, 497, 212-220. doi: 10.1016/j.canlet.2020.10.032 PMID: 33132120
  44. Liu, Y.; Li, Y.; Chang, H.; Zhao, J.; Hou, J.; Yu, K.; Sun, J.; Wang, H.; Li, A. Roscovitine protects from arterial injury by regulating the expressions of c-Jun and p27 and inhibiting vascular smooth muscle cell proliferation. J. Cardiovasc. Pharmacol., 2017, 69(3), 161-169. doi: 10.1097/FJC.0000000000000453 PMID: 28009720
  45. Le Moigne, V.; Rodriguez Rincon, D.; Glatigny, S.; Dupont, C.M.; Langevin, C.; Ait Ali Said, A.; Renshaw, S.A.; Floto, R.A.; Herrmann, J.L.; Bernut, A. Roscovitine worsens Mycobacterium abscessus infection by reducing DUOX2-mediated neutrophil response. Am. J. Respir. Cell Mol. Biol., 2022, 66(4), 439-451. doi: 10.1165/rcmb.2021-0406OC PMID: 35081328
  46. Le Roy, L.; Letondor, A.; Le Roux, C.; Amara, A.; Timsit, S. Cellular and molecular mechanisms of R/S-roscovitine and CDKs related inhibition under both focal and global cerebral ischemia: A focus on neurovascular unit and immune cells. Cells, 2021, 10(1), 104. doi: 10.3390/cells10010104 PMID: 33429982
  47. Abaza, M.S.I.; Bahman, A.M.A.; Al-Attiyah, R.J. Roscovitine synergizes with conventional chemo-therapeutic drugs to induce efficient apoptosis of human colorectal cancer cells. World J. Gastroenterol., 2008, 14(33), 5162-5175. doi: 10.3748/wjg.14.5162 PMID: 18777593
  48. Vella, S.; Tavanti, E.; Hattinger, C.M.; Fanelli, M.; Versteeg, R.; Koster, J.; Picci, P.; Serra, M. Targeting CDKs with roscovitine increases sensitivity to DNA damaging drugs of human osteosarcoma cells. PLoS One, 2016, 11(11), e0166233. doi: 10.1371/journal.pone.0166233 PMID: 27898692

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers