The Prognostic Roles of PYCR2 and ZBTB18 Expression in Tissues of Colorectal Carcinoma and Non-Neoplastic Tissues: An Immunohistochemical Study

Abstract

Background It is important to detect novel biomarkers responsible for the progression and spread of colorectal cancer (CRC) to better evaluate the prognosis of the patients, provide better management, and foster the development of therapeutic targets. In humans, pyrroline-5-carboxylate reductase 2 (PYCR2) is encoded on chromosome 1q42.12, and its metabolic activity has been linked to oncogenesis in many cancers. Zinc finger and broad-complex, tramtrack, and bric-à-brac (BTB) domain-containing protein 18 (ZBTB18), a zinc finger transcriptional repressor, has been found to have a tumor-suppressor role and to be methylated in CRCs. To date, the prognostic roles of PYCR2 and ZBTB18 in CRC patients have not been thoroughly studied.

Objective To evaluate the tissue protein expression of PYCR2 and ZBTB18 in CRC and adjacent non-neoplastic intestinal tissues, to detect their roles in CRC carcinogenesis, progression and metastases.

Patients and methods After applying the inclusion criteria, 60 CRC patients were included in the study. Tissue samples from the tumor and the adjacent non-neoplastic tissues were stained with PYCR2 and ZBTB18. The patients were followed up for about 30 months (range: 10 to 36 months). We performed a correlation regarding the expression of the markers, and clinicopathological and prognostic parameters.

Results Upregulation of PYCR2 and downregulation of ZBTB18 were found to be higher in CRC tissue than in the adjacent non-neoplastic colonic mucosa (p = 0.026 and p < 0.001 respectively). High expression of PYCR2 and low expression of ZBTB18 were positively correlated with large tumor size, higher tumor grade, advanced tumor stage, presence of spread to lymph nodes, and presence of distant metastases (p < 0.001). High PYCR2 and low ZBTB18 expressions were significantly associated with poor response to therapy (p = 0.008 and 0.0.17 respectively), as well as high incidence of progression and recurrence (p = 0.005), and unfavorable overall survival (OS) rates (p = 0.001).

Conclusion High expression of PYCR2 and low expression of ZBTB18 were independent predictors of CRC, progression, poor prognosis and unfavorable patient OS and progression-free survival (PFS) rates.

Keywords

colorectal cancer - PYCR2 - ZBTB18 - immunohistochemistry - prognosis

Publikationsverlauf

Eingereicht: 16. Oktober 2021

Angenommen: 03. März 2022

Artikel online veröffentlicht:
01. August 2022

• References

• 1 Martínez-Barriocanal Á, Arango D, Dopeso H. PVT1 long non-coding RNA in gastrointestinal cancer. Front Oncol 2020; 10: 38
• 2 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68 (06) 394-424
• 3 Tauriello DVF, Palomo-Ponce S, Stork D. et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 2018; 554 (7693): 538-543
• 4 Phang JM, Pandhare J, Liu Y. The metabolism of proline as microenvironmental stress substrate. J Nutr 2008; 138 (10) 2008S-2015S
• 5 Loayza-Puch F, Rooijers K, Buil LC. et al. Tumour-specific proline vulnerability uncovered by differential ribosome codon reading. Nature 2016; 530 (7591): 490-494
• 6 Tang L, Zeng J, Geng P. et al. Global metabolic profiling identifies a pivotal role of proline and hydroxyproline metabolism in supporting hypoxic response in hepatocellular carcinoma. Clin Cancer Res 2018; 24 (02) 474-485
• 7 Wang S, Gu L, Huang L, Fang J, Liu Z, Xu Q. The upregulation of PYCR2 is associated with aggressive colon cancer progression and a poor prognosis. Biochem Biophys Res Commun 2021; 572 (05) 20-26
• 8 Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012; 487 (7407): 330-337
• 9 Irizarry RA, Ladd-Acosta C, Wen B. et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 2009; 41 (02) 178-186
• 10 Bazzocco S, Dopeso H, Martínez-Barriocanal Á. et al. Identification of ZBTB18 as a novel colorectal tumor suppressor gene through genome-wide promoter hypermethylation analysis. Clin Epigenetics 2021; 13 (01) 88
• 11 Edge SB, Compton CC. The American Joint Committee on Cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010; 17: 1471-1474
• 12 Li J, Hu B, Fang L, Gao Y, Shi SH, He H. et al. Barrier-to-autointegration factor 1: A novel biomarker for gastric cancer. Oncol Lett 2018; 15 (05) 6488-6494
• 13 Yin F, Huang X, Xuan Y. Pyrroline-5-Carboxylate Reductase-2 Promotes Colorectal Cancer Progression via Activating PI3K/AKT/mTOR Pathway. Dis Markers 2021; 2021: 9950663
• 14 D'Aniello C, Patriarca EJ, Phang JM, Minchiotti G. Proline metabolism in tumor growth and metastatic progression. Front Oncol 2020; 10 (15) 776-789
• 15 Craze ML, Cheung H, Jewa N. et al. MYC regulation of glutamine-proline regulatory axis is key in luminal B breast cancer. Br J Cancer 2018; 118 (02) 258-265
• 16 Sharif T, Martell E, Dai C, Singh SK, Gujar S. Regulation of the proline regulatory axis and autophagy modulates stemness in TP73/p73 deficient cancer stem-like cells. Autophagy 2019; 15 (05) 934-936
• 17 Nakayama T, Al-Maawali A, El-Quessny M. et al. Mutations in PYCR2, encoding pyrroline-5-carboxylate reductase 2, cause microcephaly and hypomyelination. Am J Hum Genet 2015; 96 (05) 709-719
• 18 Zhang J, Tian XJ, Xing J. Signal transduction pathways of EMT induced by TGF-beta, SHH, and WNT and their crosstalks. J Clin Med 2016; 5 (04) E41
• 19 R. Jackstadt, S.R. van Hooff, J.D. Leach, X. Cortes-Lavaud, J.O. Lohuis, R.A. Ridgway et al. Epithelial NOTCH signaling rewires the tumor microenvironment of colorectal cancer to drive poor-prognosis subtypes and metastasis. Cancer Cell 2019; 36 (03) 319-336e7
• 20 Farooqi AA, de la Roche M, Djamgoz MBA, Siddik ZH. Overview of the oncogenic signaling pathways in colorectal cancer: Mechanistic insights. Semin Cancer Biol 2019; 58 (58) 65-79
• 21 J.M. Phang. Proline metabolism in cell regulation and cancer biology: recent advances and hypotheses. Antioxidants Redox Signal 2019; 30 (04) 635-649
• 22 Satoh K, Yachida S, Sugimoto M. et al. Global metabolic reprogramming of colorectal cancer occurs at adenoma stage and is induced by MYC. Proc Natl Acad Sci U S A 2017; 114 (37) E7697-E7706
• 23 Umezawa K, Lin Y. Inhibition of matrix metalloproteinase expression and cellular invasion by NF-κB inhibitors of microbial origin. Biochim Biophys Acta Proteins Proteomics 2020; 1868 (06) 140412
• 24 Yokoyama S, Ito Y, Ueno-Kudoh H. et al. A systems approach reveals that the myogenesis genome network is regulated by the transcriptional repressor RP58. Dev Cell 2009; 17 (06) 836-848
• 25 Xiang C, Baubet V, Pal S. et al. RP58/ZNF238 directly modulates proneurogenic gene levels and is required for neuronal differentiation and brain expansion. Cell Death Differ 2012; 19 (04) 692-702
• 26 Fedele V, Dai F, Masilamani AP. et al. Epigenetic regulation of ZBTB18 promotes glioblastoma progression. Mol Cancer Res 2017; 15 (08) 998-1011
• 27 Giannakis M, Mu XJ, Shukla SA. et al. Genomic correlates of immunecell infiltrates in colorectal carcinoma. Cell Rep 2016; 17 (04) 1206