Overexpression of Hydroxyproline Via EGLN/HIF1A is Associated with Distant Metastasis in Pancreatic Cancer

Overview

Journal Am J Cancer Res

Specialty Oncology

Date 2020 Sep 9

PMID 32905516

Citations 10

Authors

Naokazu Chiba

Makoto Sunamura

Masashi Nakagawa

Itsuki Koganezawa

Kei Yokozuka

Toshimichi Kobayashi

Kosuke Hikita

Yosuke Ozawa

Masaaki Okihara

Toru Sano

Koichi Tomita

Rina Tsutsui

Masahiro Sugimoto

Shigeyuki Kawachi

Affiliations

Soon will be listed here.

Abstract

For pancreatic cancer, the probability of distant metastasis can help choose the best course of treatment. The aim of this study is to establish the efficacy of hydroxyproline as a biomarker for distant metastasis for pancreatic cancer and to clarify the mechanism of EGLN/HIF1A axis that controls the invasion and metastasis. Metabolites (hydroxyproline) and genes (EGLN2 and EGLN3) were identified by metabolome analysis of the serum with pancreatic cancers with and without distant metastasis. The mechanism of EGLN/HIF1A axis including angiogenesis was examined in pancreatic cancer cells. Hydroxyproline associated with these mechanisms was evaluated to suggest the association with overall survival in pancreatic cancer. Decreased expression of EGLN2 and EGLN3 in pancreatic cancer, via the HIF1A and TGF ß1 pathway, was associated with the induction of angiogenic factors, increased vascular invasion, and poor overall patient survival. Hydroxyproline concentrations were regulated via the HIF1A pathway by EGLN2 and EGLN3, and that increased concentrations of hydroxyproline promote the invasion and metastasis of pancreatic cancer cells. These results suggested that the expression of hydroxyproline through the HIF1A pathway induced by EGLN2 and EGLN3 could be a surrogate marker for treatment and might predict distant metastasis in pancreatic cancer.

Citing Articles

Elevated Expression of Cell Adhesion, Metabolic, and Mucus Secretion Gene Clusters Associated with Tumorigenesis, Metastasis, and Poor Survival in Pancreatic Ductal Adenocarcinoma.

Balakrishnan K, Xiao Y, Chen Y, Dong J Cancers (Basel). 2024; 16(23).

PMID: 39682235 PMC: 11640259. DOI: 10.3390/cancers16234049.

Comprehensive analysis and experimental verification reveal the molecular characteristics of EGLN3 in pan-cancer and its relationship with the proliferation and apoptosis of lung cancer.

Shi Y, Dai P, Chen T, Yan J Heliyon. 2024; 10(12):e33206.

PMID: 39021988 PMC: 11253545. DOI: 10.1016/j.heliyon.2024.e33206.

Understanding Hypoxia-Driven Tumorigenesis: The Interplay of HIF1A, DNA Methylation, and Prolyl Hydroxylases in Head and Neck Squamous Cell Carcinoma.

Ostapowicz J, Ostrowska K, Rawluszko-Wieczorek A, Wojtera B, Koczot S, Golusinski W Int J Mol Sci. 2024; 25(12).

PMID: 38928200 PMC: 11203966. DOI: 10.3390/ijms25126495.

Association between CT-based adipose variables, preoperative blood biochemical indicators and pathological T stage of clear cell renal cell carcinoma.

Sun Z, Zhang Y, Xia Y, Ba X, Zheng Q, Liu J Heliyon. 2024; 10(2):e24456.

PMID: 38268833 PMC: 10803934. DOI: 10.1016/j.heliyon.2024.e24456.

EGLN3 attenuates gastric cancer cell malignant characteristics by inhibiting JMJD8/NF-κB signalling activation independent of hydroxylase activity.

Cai F, Yang X, Ma G, Wang P, Zhang M, Zhang N Br J Cancer. 2024; 130(4):597-612.

PMID: 38184692 PMC: 10876699. DOI: 10.1038/s41416-023-02546-x.

References

Erez N, Milyavsky M, Eilam R, Shats I, Goldfinger N, Rotter V . Expression of prolyl-hydroxylase-1 (PHD1/EGLN2) suppresses hypoxia inducible factor-1alpha activation and inhibits tumor growth. Cancer Res. 2003; 63(24):8777-83. View

Olive K, Jacobetz M, Davidson C, Gopinathan A, McIntyre D, Honess D . Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009; 324(5933):1457-61. PMC: 2998180. DOI: 10.1126/science.1171362. View

Saito J, Imamura Y, Itoh J, Matsuyama S, Maruta A, Hayashi T . ELISA measurement for urinary 3-hydroxyproline-containing peptides and its preliminary application to healthy persons and cancer patients. Anticancer Res. 2010; 30(3):1007-14. View

Itoi T, Sugimoto M, Umeda J, Sofuni A, Tsuchiya T, Tsuji S . Serum Metabolomic Profiles for Human Pancreatic Cancer Discrimination. Int J Mol Sci. 2017; 18(4). PMC: 5412351. DOI: 10.3390/ijms18040767. View

Xie X, Xiao H, Ding F, Zhong H, Zhu J, Ma N . Over-expression of prolyl hydroxylase-1 blocks NF-κB-mediated cyclin D1 expression and proliferation in lung carcinoma cells. Cancer Genet. 2014; 207(5):188-94. DOI: 10.1016/j.cancergen.2014.04.008. View

Chiba N, Comaills V, Shiotani B, Takahashi F, Shimada T, Tajima K . Homeobox B9 induces epithelial-to-mesenchymal transition-associated radioresistance by accelerating DNA damage responses. Proc Natl Acad Sci U S A. 2011; 109(8):2760-5. PMC: 3286905. DOI: 10.1073/pnas.1018867108. View

Kulemann B, Hoeppner J, Wittel U, Glatz T, Keck T, Wellner U . Perioperative and long-term outcome after standard pancreaticoduodenectomy, additional portal vein and multivisceral resection for pancreatic head cancer. J Gastrointest Surg. 2015; 19(3):438-44. DOI: 10.1007/s11605-014-2725-8. View

Su Y, Loos M, Giese N, Hines O, Diebold I, Gorlach A . PHD3 regulates differentiation, tumour growth and angiogenesis in pancreatic cancer. Br J Cancer. 2010; 103(10):1571-9. PMC: 2990580. DOI: 10.1038/sj.bjc.6605936. View

Semenza G . Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2009; 29(5):625-34. PMC: 2969168. DOI: 10.1038/onc.2009.441. View

10.

Siegel R, Ma J, Zou Z, Jemal A . Cancer statistics, 2014. CA Cancer J Clin. 2014; 64(1):9-29. DOI: 10.3322/caac.21208. View

11.

Postlewait L, Ethun C, Kooby D, Sarmiento J, Chen Z, Staley 3rd C . Combination gemcitabine/cisplatin therapy and ERCC1 expression for resected pancreatic adenocarcinoma: Results of a Phase II prospective trial. J Surg Oncol. 2016; 114(3):336-41. DOI: 10.1002/jso.24317. View

12.

Kamisawa T, Wood L, Itoi T, Takaori K . Pancreatic cancer. Lancet. 2016; 388(10039):73-85. DOI: 10.1016/S0140-6736(16)00141-0. View

13.

Kaelin Jr W, Ratcliffe P . Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008; 30(4):393-402. DOI: 10.1016/j.molcel.2008.04.009. View

14.

Koh M, Lemos Jr R, Liu X, Powis G . The hypoxia-associated factor switches cells from HIF-1α- to HIF-2α-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion. Cancer Res. 2011; 71(11):4015-27. PMC: 3268651. DOI: 10.1158/0008-5472.CAN-10-4142. View

15.

Tang L, Zeng J, Geng P, Fang C, Wang Y, Sun M . Global Metabolic Profiling Identifies a Pivotal Role of Proline and Hydroxyproline Metabolism in Supporting Hypoxic Response in Hepatocellular Carcinoma. Clin Cancer Res. 2017; 24(2):474-485. DOI: 10.1158/1078-0432.CCR-17-1707. View

16.

Hayashida T, Takahashi F, Chiba N, Brachtel E, Takahashi M, Godin-Heymann N . HOXB9, a gene overexpressed in breast cancer, promotes tumorigenicity and lung metastasis. Proc Natl Acad Sci U S A. 2010; 107(3):1100-5. PMC: 2824265. DOI: 10.1073/pnas.0912710107. View

17.

Ravikumar R, Sabin C, Abu Hilal M, Bramhall S, White S, Wigmore S . Portal vein resection in borderline resectable pancreatic cancer: a United Kingdom multicenter study. J Am Coll Surg. 2014; 218(3):401-11. DOI: 10.1016/j.jamcollsurg.2013.11.017. View

18.

Stein S, James E, Deng Y, Cong X, Kortmansky J, Li J . Final analysis of a phase II study of modified FOLFIRINOX in locally advanced and metastatic pancreatic cancer. Br J Cancer. 2016; 114(7):737-43. PMC: 4984865. DOI: 10.1038/bjc.2016.45. View

19.

Adams E, FRANK L . Metabolism of proline and the hydroxyprolines. Annu Rev Biochem. 1980; 49:1005-61. DOI: 10.1146/annurev.bi.49.070180.005041. View

20.

Xiang J, Hu Q, Qin Y, Ji S, Xu W, Liu W . TCF7L2 positively regulates aerobic glycolysis via the EGLN2/HIF-1α axis and indicates prognosis in pancreatic cancer. Cell Death Dis. 2018; 9(3):321. PMC: 5833500. DOI: 10.1038/s41419-018-0367-6. View