Tumor Biology

, Volume 36, Issue 10, pp 7675–7683 | Cite as

The prognostic impact of lipid biosynthesis-associated markers, HSD17B2 and HMGCS2, in rectal cancer treated with neoadjuvant concurrent chemoradiotherapy

  • Ying-En Lee
  • Hong-Lin He
  • Yow-Ling Shiue
  • Sung-Wei Lee
  • Li-Ching Lin
  • Ting-Feng Wu
  • I-Wei Chang
  • Hao-Hsien Lee
  • Chien-Feng Li
Research Article

Abstract

Neoadjuvant concurrent chemoradiotherapy has been widely used for rectal cancer to improve local tumor control. The varied response of individual tumors encouraged us to search for useful biomarkers to predict the therapeutic response. The study was aimed to evaluate the prognostic impact of lipid biosynthesis-associated biomarkers in rectal cancer patients treated with preoperative chemoradiotherapy. Through analysis of the previously published gene expression profiling database focusing on genes associated with lipid biosynthesis, we found that HSD17B2 and HMGCS2 were the top two significantly upregulated genes in the non-responders. We further evaluated their expression by immunohistochemistry in the pre-treatment tumor specimens from 172 patients with rectal cancer and statistically analyzed the associations between their expression and various clinicopathological factors, as well as survival. High expression of HMGCS2 or HSD17B2 was significantly associated with advanced pre- and post-treatment tumor or nodal status (P < 0.001) and lower tumor regression grade (P < 0.001). More importantly, high expression of either HMGCS2 or HSD17B2 was of prognostic significance, with HMGCS2 overexpression indicating poor prognosis for disease-free survival (P = 0.0003), local recurrence-free survival (P = 0.0115), and metastasis-free survival (P = 0.0119), while HSD17B2 overexpression was associated with poor prognosis for disease-free survival (P <0.0001), local recurrence-free survival (P = 0.0009), and metastasis-free survival (P < 0.0001). In multivariate analysis, only HSD17B2 overexpression remained as an independent prognosticator for shorter disease-free survival (P < 0.001) and metastasis-free survival (P = 0.008). In conclusion, high expression of either HSD17B2 or HMGCS2 predicted poor susceptibility of rectal cancer to preoperative chemoradiotherapy. Both acted as promising prognostic factors, particularly HSD17B2.

Keywords

HSD17B2 HMGCS2 Rectal cancer Chemoradiotherapy CCRT 

Abbreviations

CCRT

Concurrent chemoradiotherapy

HSD17B2

17β-hydroxysteroid dehydrogenase type 2

E2

Estradiol

E1

Estrone

HMGCS2

3-hydroxy-3-methylglutaryl-CoA synthase

EUS

Endoscopic ultrasound

Pre-Tx

Pretreatment

Post-Tx

Posttreatment

AJCC

American Joint Committee on Cancer

TRG

Tumor regression grade

DFS

Disease-free survival

LRFS

Local recurrence-free survival

MeFS

Metastasis-free survival

ERß

Estrogen receptor beta

Notes

Acknowledgments

This study is supported by the Chi Mei Medical Center (CMFHR10303), Ministry of Health and Welfare (Health and welfare surcharge of tobacco products, MOHW104-TDU-B-212-124-003), and E-Da Hospital (EDAHP104022). The authors are grateful to the BioBank of Chi Mei Medical Center for providing the tumor samples.

Conflicts of interest

None

Supplementary material

13277_2015_3503_Fig4_ESM.gif (155 kb)
Figure S1

Survival analysis plotted by using Kaplan-Meier methods. When categorizing the expression of HSD17B2 or HMGCS2 into three groups, namely low, medium, and high expression. Either high expression of HSD17B2 or HMGCS2 remained significantly predictive for inferior disease-free (A, D), local recurrence-free (B, E), and metastasis-free survival (C, F, respectively). (GIF 155 kb)

13277_2015_3503_MOESM1_ESM.tif (2.5 mb)
High resolution image (TIFF 2576 kb)
13277_2015_3503_MOESM2_ESM.doc (88 kb)
Table S1 (DOC 87 kb)

References

  1. 1.
    Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351:1731–40.CrossRefPubMedGoogle Scholar
  2. 2.
    Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355:1114–23.CrossRefPubMedGoogle Scholar
  3. 3.
    Gerard JP, Conroy T, Bonnetain F, Bouche O, Chapet O, Closon-Dejardin MT, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006;24:4620–5.CrossRefPubMedGoogle Scholar
  4. 4.
    Read TE, McNevin MS, Gross EK, Whiteford HM, Lewis JL, Ratkin G, et al. Neoadjuvant therapy for adenocarcinoma of the rectum: tumor response and acute toxicity. Dis Colon Rectum. 2001;44:513–22.CrossRefPubMedGoogle Scholar
  5. 5.
    Li JN, Mahmoud MA, Han WF, Ripple M, Pizer ES. Sterol regulatory element-binding protein-1 participates in the regulation of fatty acid synthase expression in colorectal neoplasia. Exp Cell Res. 2000;261:159–65.CrossRefPubMedGoogle Scholar
  6. 6.
    Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 2007;7:763–77.CrossRefPubMedGoogle Scholar
  7. 7.
    Swinnen JV, Vanderhoydonc F, Elgamal AA, Eelen M, Vercaeren I, Joniau S, et al. Selective activation of the fatty acid synthesis pathway in human prostate cancer. Int J Cancer. 2000;88:176–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Yoon S, Lee MY, Park SW, Moon JS, Koh YK, Ahn YH, et al. Up-regulation of acetyl-CoA carboxylase alpha and fatty acid synthase by human epidermal growth factor receptor 2 at the translational level in breast cancer cells. J Biol Chem. 2007;282:26122–31.CrossRefPubMedGoogle Scholar
  9. 9.
    Watanabe T, Komuro Y, Kiyomatsu T, Kanazawa T, Kazama Y, Tanaka J, et al. Prediction of sensitivity of rectal cancer cells in response to preoperative radiotherapy by DNA microarray analysis of gene expression profiles. Cancer Res. 2006;66:3370–4.CrossRefPubMedGoogle Scholar
  10. 10.
    Peltoketo H, Luu-The V, Simard J, Adamski J. 17beta-hydroxysteroid dehydrogenase (HSD)/17-ketosteroid reductase (KSR) family; nomenclature and main characteristics of the 17HSD/KSR enzymes. J Mol Endocrinol. 1999;23:1–11.CrossRefPubMedGoogle Scholar
  11. 11.
    Oduwole OO, Mäkinen MJ, Isomaa VV, Pulkka A, Jernvall P, Karttunen TJ, et al. 17β-Hydroxysteroid dehydrogenase type 2: independent prognostic significance and evidence of estrogen protection in female patients with colon cancer. J Steroid Biochem Mol Biol. 2003;87:133–40.CrossRefPubMedGoogle Scholar
  12. 12.
    Hegardt FG. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme in ketogenesis. Biochem J. 1999;338(Pt 3):569–82.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Camarero N, Mascaro C, Mayordomo C, Vilardell F, Haro D, Marrero PF. Ketogenic HMGCS2 Is a c-Myc target gene expressed in differentiated cells of human colonic epithelium and down-regulated in colon cancer. Mol Cancer Res. 2006;4:645–53.CrossRefPubMedGoogle Scholar
  14. 14.
    Sheu MJ, Li CF, Lin CY, Lee SW, Lin LC, Chen TJ, et al. Overexpression of ANXA1 confers independent negative prognostic impact in rectal cancers receiving concurrent chemoradiotherapy. Tumour Biol. 2014;35:7755–63.CrossRefPubMedGoogle Scholar
  15. 15.
    Lin CY, Sheu MJ, Li CF, Lee SW, Lin LC, Wang YF, et al. Deficiency in asparagine synthetase expression in rectal cancers receiving concurrent chemoradiotherapy: negative prognostic impact and therapeutic relevance. Tumour Biol. 2014;35:6823–30.CrossRefPubMedGoogle Scholar
  16. 16.
    Dworak O, Keilholz L, Hoffmann A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Color Dis. 1997;12:19–23.CrossRefGoogle Scholar
  17. 17.
    Lin LC, Lee HH, Hwang WS, Li CF, Huang CT, Que J, et al. p53 and p27 as predictors of clinical outcome for rectal-cancer patients receiving neoadjuvant therapy. Surg Oncol. 2006;15:211–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell. 2008;13:472–82.CrossRefPubMedGoogle Scholar
  19. 19.
    Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Santos CR, Schulze A. Lipid metabolism in cancer. FEBS J. 2012;279:2610–23.CrossRefPubMedGoogle Scholar
  21. 21.
    Rysman E, Brusselmans K, Scheys K, Timmermans L, Derua R, Munck S, et al. De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation. Cancer Res. 2010;70:8117–26.CrossRefPubMedGoogle Scholar
  22. 22.
    Guo JY, Li X, Browning Jr JD, Rottinghaus GE, Lubahn DB, Constantinou A, et al. Dietary soy isoflavones and estrone protect ovariectomized ERalphaKO and wild-type mice from carcinogen-induced colon cancer. J Nutr. 2004;134:179–82.PubMedGoogle Scholar
  23. 23.
    Smirnoff P, Liel Y, Gnainsky J, Shany S, Schwartz B. The protective effect of estrogen against chemically induced murine colon carcinogenesis is associated with decreased CpG island methylation and increased mRNA and protein expression of the colonic vitamin D receptor. Oncol Res. 1999;11:255–64.PubMedGoogle Scholar
  24. 24.
    Weyant MJ, Carothers AM, Mahmoud NN, Bradlow HL, Remotti H, Bilinski RT, et al. Reciprocal expression of ERalpha and ERbeta is associated with estrogen-mediated modulation of intestinal tumorigenesis. Cancer Res. 2001;61:2547–51.PubMedGoogle Scholar
  25. 25.
    Oduwole OO, Isomaa VV, Nokelainen PA, Stenback F, Vihko PT. Downregulation of estrogen-metabolizing 17 beta-hydroxysteroid dehydrogenase type 2 expression correlates inversely with Ki67 proliferation marker in colon-cancer development. Int J Cancer. 2002;97:1–6.CrossRefPubMedGoogle Scholar
  26. 26.
    English MA, Hughes SV, Kane KF, Langman MJ, Stewart PM, Hewison M. Oestrogen inactivation in the colon: analysis of the expression and regulation of 17beta-hydroxysteroid dehydrogenase isozymes in normal colon and colonic cancer. Br J Cancer. 2000;83:550–8.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Wilkins HR, Doucet K, Duke V, Morra A, Johnson N. Estrogen prevents sustained COLO-205 human colon cancer cell growth by inducing apoptosis, decreasing c-myb protein, and decreasing transcription of the anti-apoptotic protein bcl-2. Tumour Biol. 2010;31:16–22.CrossRefPubMedGoogle Scholar
  28. 28.
    Hsu HH, Cheng SF, Wu CC, Chu CH, Weng YJ, Lin CS, et al. Apoptotic effects of over-expressed estrogen receptor-beta on LoVo colon cancer cell is mediated by p53 signalings in a ligand-dependent manner. Chin J Physiol. 2006;49:110–6.PubMedGoogle Scholar
  29. 29.
    Marino M, Galluzzo P, Leone S, Acconcia F, Ascenzi P. Nitric oxide impairs the 17beta-estradiol-induced apoptosis in human colon adenocarcinoma cells. Endocr Relat Cancer. 2006;13:559–69.CrossRefPubMedGoogle Scholar
  30. 30.
    Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A. 1996;93:5925–30.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Ying-En Lee
    • 1
  • Hong-Lin He
    • 2
    • 3
  • Yow-Ling Shiue
    • 3
  • Sung-Wei Lee
    • 4
  • Li-Ching Lin
    • 4
  • Ting-Feng Wu
    • 5
  • I-Wei Chang
    • 2
  • Hao-Hsien Lee
    • 6
  • Chien-Feng Li
    • 5
    • 7
    • 8
    • 9
  1. 1.Department of AnesthesiologyKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungTaiwan
  2. 2.Department of Pathology, E-DA HospitalI-Shou UniversityKaohsiungTaiwan
  3. 3.Institute of Biomedical ScienceNational Sun Yat-sen UniversityKaohsiungTaiwan
  4. 4.Department of Radiation OncologyChi Mei Medical CenterLiouyingTaiwan
  5. 5.Department of BiotechnologySouthern Taiwan University of Science and TechnologyTainanTaiwan
  6. 6.Department of SurgeryChi Mei Medical CenterLiouyingTaiwan
  7. 7.Graduate Institute of Clinical Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  8. 8.National Institute of Cancer ResearchNational Health Research InstitutesTainanTaiwan
  9. 9.Department of PathologyChi Mei Medical CenterTainanTaiwan

Personalised recommendations