J Pathol Transl Med.  2017 Jul;51(4):359-364. 10.4132/jptm.2017.03.16.

Implication of PHF2 Expression in Clear Cell Renal Cell Carcinoma

• Lee C
• Kim B
• Song B
• Moon KC

• KMID: 2392575
• DOI: http://doi.org/10.4132/jptm.2017.03.16

Abstract

BACKGROUND
Clear cell renal cell carcinoma (CCRCC) is presumed to be associated with adipogenic differentiation. Histone modification is known to be important for adipogenesis, and the function of histone demethylase plant homeodomain finger 2 (PHF2) has been noted. In addition, PHF2 may act as a tumor suppressor via epigenetic regulation of p53 and is reported to be reduced in colon cancer and stomach cancer tissues. In this study, we examined PHF2 expression in CCRCC specimens by immunohistochemistry.
METHODS
We studied 254 CCRCCs and 56 non-neoplastic renal tissues from patients who underwent radical or partial nephrectomy between 2000 and 2003 at the Seoul National University Hospital. Tissue microarray blocks were prepared, and immunohistochemical staining for PHF2 was performed.
RESULTS
Among 254 CCRCC cases, 150 cases (59.1%) showed high expression and 104 cases (40.1%) showed low expression. High expression of PHF2 was significantly correlated with a low Fuhrman nuclear grade (p < .001), smaller tumor size (p < .001), low overall stage (p = .003), longer cancer-specific survival (p = .002), and progression-free survival (p < .001) of the patients. However, it was not an independent prognostic factor in multivariate analysis adjusted for Fuhrman nuclear grade and overall stage.
CONCLUSIONS
Our study showed that low expression of PHF2 is associated with aggressiveness and poor prognosis of CCRCC.

Keyword

PHF2 protein, human; Carcinoma, renal cell; Clear cell renal cell carcinoma; Immunohistochemistry; Adipogenesis

MeSH Terms

Adipogenesis
Carcinoma, Renal Cell*
Colonic Neoplasms
Disease-Free Survival
Epigenomics
Fingers
Histones
Humans
Immunohistochemistry
Multivariate Analysis
Nephrectomy
Plants
Prognosis
Seoul
Stomach Neoplasms
Histones

Figure

• 

  Fig. 1. Plant homeodomain finger 2 (PHF2) expression in non-neoplastic renal tissue. PHF2 is expressed in the nucleus and cytoplasm of the proximal tubular epithelium and in the nucleus of the distal tubular epithelium and podocytes in the glomerulus. (A) Cortex. (B) Medulla.

• 

  Fig. 2. Plant homeodomain finger 2 expression in clear cell renal cell carcinoma. (A) High expression (B) Low expression.

• 

  Fig. 3. Kaplan-Meier curves. Cancer-specific and progression-free survival according to plant homeodomain finger 2 (PHF2) expression.

Reference

1. Jung KW, Kong HJ, Oh CM, Seo HG, Lee JS. Cancer statistics in Korea: incidence, mortality, survival and prevalence in 2010. Cancer Res Treat. 2013; 45:1–14.

2. Lee C, Park JW, Suh JH, Nam KH, Moon KC. Histologic variations and immunohistochemical features of metastatic clear cell renal cell carcinoma. Korean J Pathol. 2013; 47:426–32.

3. Eble JN, Sauter G, Epstein JI, Sesterhenn IA. Pathology and genetics of tumours of the urinary system and male genital organs. Lyon: IARC Press;2004. p. 12–39.

4. Rezende RB, Drachenberg CB, Kumar D, et al. Differential diagnosis between monomorphic clear cell adenocarcinoma of salivary glands and renal (clear) cell carcinoma. Am J Surg Pathol. 1999; 23:1532–8.

5. Yao M, Tabuchi H, Nagashima Y, et al. Gene expression analysis of renal carcinoma: adipose differentiation-related protein as a potential diagnostic and prognostic biomarker for clear-cell renal carcinoma. J Pathol. 2005; 205:377–87.

6. Yao M, Shioi K, et al. Expression of adipose differentiation-related protein: a predictor of cancer-specific survival in clear cell renal carcinoma. Clin Cancer Res. 2007; 13:152–60.

7. Tun HW, Marlow LA, von Roemeling CA, et al. Pathway signature and cellular differentiation in clear cell renal cell carcinoma. PLoS One. 2010; 5:e10696.

8. Hasenpusch-Theil K, Chadwick BP, Theil T, Heath SK, Wilkinson DG. PHF2, a novel PHD finger gene located on human chromosome 9q22. Mamm Genome. 1999; 10:294–8.

9. Okuno Y, Ohtake F, Igarashi K, et al. Epigenetic regulation of adipogenesis by PHF2 histone demethylase. Diabetes. 2013; 62:1426–34.

10. Okuno Y, Inoue K, Imai Y. Novel insights into histone modifiers in adipogenesis. Adipocyte. 2013; 2:285–8.

11. Baba A, Ohtake F, Okuno Y, et al. PKA-dependent regulation of the histone lysine demethylase complex PHF2-ARID5B. Nat Cell Biol. 2011; 13:668–75.

12. Pascual G, Liu W, et al. Control of proinflammatory gene programs by regulated trimethylation and demethylation of histone H4K20. Mol Cell. 2012; 48:28–38.

13. Sinha S, Singh RK, Alam N, Roy A, Roychoudhury S, Panda CK. Alterations in candidate genes PHF2, FANCC, PTCH1 and XPA at chromosomal 9q22.3 region: pathological significance in early- and late-onset breast carcinoma. Mol Cancer. 2008; 7:84.

14. Sun LL, Sun XX, Xu XE, et al. Overexpression of JumonjiAT-rich interactive domain 1B and PHD finger protein 2 is involved in the progression of esophageal squamous cell carcinoma. Acta Histochem. 2013; 115:56–62.

15. Ghosh A, Maiti GP, Bandopadhyay MN, et al. Inactivation of 9q22.3 tumor suppressor genes predict outcome for patients with head and neck squamous cell carcinoma. Anticancer Res. 2013; 33:1215–20.

16. Lee KH, Park JW, Sung HS, et al. PHF2 histone demethylase acts as a tumor suppressor in association with p53 in cancer. Oncogene. 2015; 34:2897–909.

17. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A 3rd. AJCC cancer staging manual. 7th ed. New York: Springer;2010. p. 479–90.

18. Musri MM, Carmona MC, Hanzu FA, Kaliman P, Gomis R, Párrizas M. Histone demethylase LSD1 regulates adipogenesis. J Biol Chem. 2010; 285:30034–41.

19. Brasaemle DL, Barber T, Wolins NE, Serrero G, Blanchette-Mackie EJ, Londos C. Adipose differentiation-related protein is an ubiquitously expressed lipid storage droplet-associated protein. J Lipid Res. 1997; 38:2249–63.

20. Gao J, Serrero G. Adipose differentiation related protein (ADRP) expressed in transfected COS-7 cells selectively stimulates long chain fatty acid uptake. J Biol Chem. 1999; 274:16825–30.

21. Thoenes W, Störkel S, Rumpelt HJ. Histopathology and classification of renal cell tumors (adenomas, oncocytomas and carcinomas): the basic cytological and histopathological elements and their use for diagnostics. Pathol Res Pract. 1986; 181:125–43.

22. Tripathi A, Dasgupta S, Roy A, et al. Sequential deletions in both arms of chromosome 9 are associated with the development of head and neck squamous cell carcinoma in Indian patients. J Exp Clin Cancer Res. 2003; 22:289–97.

23. Baytekin F, Tuna B, Mungan U, Aslan G, Yorukoglu K. Significance of P-glycoprotein, p53, and survivin expression in renal cell carcinoma. Urol Oncol. 2011; 29:502–7.

24. Noon AP, Polanski R, El-Fert AY, et al. Combined p53 and MDM2 biomarker analysis shows a unique pattern of expression associated with poor prognosis in patients with renal cell carcinoma undergoing radical nephrectomy. BJU Int. 2012; 109:1250–7.

25. Noon AP, Vlatkovic N, Polanski R, et al. p53 and MDM2 in renal cell carcinoma: biomarkers for disease progression and future therapeutic targets? Cancer. 2010; 116:780–90.