Involvement of nuclear NHERF1 in colorectal cancer progression

Mangia,Anita; Saponaro,Concetta; Malfettone,Andrea; Bisceglie,Domenico; Bellizzi,Antonia; Asselti,Mariaconsilia; Popescu,Ondina; Reshkin,Stephan J.; Paradiso,Angelo; Simone,Giovanni

doi:10.3892/or.2012.1895

Involvement of nuclear NHERF1 in colorectal cancer progression

Authors:
- Anita Mangia
- Concetta Saponaro
- Andrea Malfettone
- Domenico Bisceglie
- Antonia Bellizzi
- Mariaconsilia Asselti
- Ondina Popescu
- Stephan J. Reshkin
- Angelo Paradiso
- Giovanni Simone
View Affiliations

Affiliations: Functional Biomorphology Laboratory, National Cancer Centre, Bari, Italy, Department of Pathology, National Cancer Centre, Bari, Italy, Department of General and Environmental Physiology, University of Bari, Bari, Italy, Scientific Direction, National Cancer Centre, 70124 Bari, Italy
Published online on: July 3, 2012 https://doi.org/10.3892/or.2012.1895
Pages: 889-894

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

NHERF1 (Na+/H+ exchanger regulatory factor 1) is expressed in the luminal membrane of many epithelia, and associated with proteins involved in tumor progression. Alterations of NHERF1 expression in different sites of metastatic colorectal cancer (mCRC) suggest a dynamic role of this protein in colon carcinogenesis. We focused on the observation of the altered expression of NHERF1 from non-neoplastic tissues to metastatic sites by immunohistochemistry. Moreover, we studied, by immunofluorescence, the colocalization between NHERF1 and the epidermal growth factor receptor (EGFR), whose overexpression is implicated in CRC progression. NHERF1 showed a different localization and expression in the examined sites. The distant non-neoplastic tissues showed NHERF1 mostly expressed at the apical membrane, while in surrounding non-neoplastic tissue decreased the apical membrane and increased cytoplasmic immunoreactivity. In adenomas a shift from apical membrane to cytoplasmic localization and nuclear expression were observed. Cytoplasmic staining in the tumor, and metastatic sites was stronger than surrounding non-neoplastic tissue. Furthermore, nuclear NHERF1 expression was noted in 80% of all samples and surprisingly, it appeared already in adenoma lesions, suggesting that NHERF1 represents an early marker of pre-morphological triggering of colorectal carcinogenesis. Then, in few tumors a positive direct correlation between membrane NHERF1 and EGFR expression was evidenced by their colocalization. Nuclear NHERF1 expression, present in the early stages of carcinogenesis and related with poor prognosis, may contribute to the onset of malignant phenotype. Specifically, we hypothesize the direct involvement of nuclear NHERF1 in both carcinogenesis and progression and its role as a potential colorectal cancer marker.

View Figures

View References

1	Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T and Thun MJ: Cancer statistics. CA Cancer J Clin. 58:71–96. 2008.
2	Horner MJ, Ries LAG, Krapcho M, et al: SEER cancer statistics review, 1975–2006. Bethesda, MD: National Cancer Institute. http://seercancergov/csr/1975-2006/. 2009
3	Fearon ER and Vogelstein B: A genetic model for colorectal tumorigenesis. Cell. 1:759–767. 1990. View Article : Google Scholar : PubMed/NCBI
4	Sjöblom T, Jones S, Wood LD, et al: The consensus coding sequences of human breast and colorectal cancers. Science. 13:268–274. 2006.
5	Bretscher A, Chambers D, Nguyen R and Reczek D: ERM-Merlin and EBP50 protein families in plasma membrane organization and function. Annu Rev Cell Dev Biol. 16:113–143. 2000. View Article : Google Scholar : PubMed/NCBI
6	Voltz JW, Weinman EJ and Shenolikar S: Expanding the role of NHERF, a PDZ-domain containing protein adapter, to growth regulation. Oncogene. 20:6309–6314. 2001. View Article : Google Scholar : PubMed/NCBI
7	Mahon MJ, Donowitz M, Yun CC and Segre GV: Na(+)/H(+) exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling. Nature. 20:858–861. 2002.
8	Shenolikar S, Voltz JW, Cunningham R and Weinman EJ: Regulation of ion transport by the NHERF family of PDZ proteins. Physiology. 19:362–369. 2004. View Article : Google Scholar : PubMed/NCBI
9	Weinman EJ, Hall RA, Friedman PA, Liu-Chen LY and Shenolikar S: The association of NHERF adaptor proteins with g protein-coupled receptors and receptor tyrosine kinases. Annu Rev Physiol. 68:491–505. 2006. View Article : Google Scholar : PubMed/NCBI
10	Mangia A, Chiriatti A, Bellizzi A, Malfettone A, Stea B, Zito FA, Reshkin SJ, Simone G and Paradiso A: Biological role of NHERF1 protein expression in breast cancer. Histopathology. 55:600–608. 2009. View Article : Google Scholar
11	Curto M, Cole BK, Lallemand D, Liu CH and McClatchey AI: Contact-dependent inhibition of EGFR signaling by Nf2/Merlin. J Cell Biol. 5:893–903. 2007. View Article : Google Scholar : PubMed/NCBI
12	Fanning AS and Anderson JM: PDZ domains: fundamental building blocks in the organization of protein complexes at the plasma membrane. J Clin Invest. 103:767–772. 1999. View Article : Google Scholar : PubMed/NCBI
13	Reczek D, Berryman M and Bretscher A: Identification of EBP50: A PDZ-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family. J Cell Biol. 6:169–179. 1997. View Article : Google Scholar : PubMed/NCBI
14	Louvet-Vallée S: ERM proteins: from cellular architecture to cell signalling. Biol Cell. 92:305–316. 2000.PubMed/NCBI
15	Mahon MJ and Segre GV: Stimulation by parathyroid hormone of a NHERF-1-assembled complex consisting of the parathyroid hormone I receptor, phospholipase Cbeta, and actin increases intracellular calcium in opossum kidney cells. J Biol Chem. 28:23550–23558. 2004. View Article : Google Scholar
16	Fouassier L, Duan CY, Feranchak AP, et al: Ezrin-radixin-moesin-binding phosphoprotein 50 is expressed at the apical membrane of rat liver epithelia. Hepatology. 33:166–176. 2001. View Article : Google Scholar : PubMed/NCBI
17	Donowitz M, Cha B, Zachos NC, Brett CL, Sharma A, Tse CM and Li X: NHERF family and NHE3 regulation. J Physiol. 567:3–11. 2005. View Article : Google Scholar : PubMed/NCBI
18	Pan Y, Wang L and Dai JL: Suppression of breast cancer cell growth by Na⁺/H⁺ exchanger regulatory factor 1 (NHERF1). Breast Cancer Res. 8:R632006. View Article : Google Scholar : PubMed/NCBI
19	Shibata T, Chuma M, Kokubu A, Sakamoto M and Hirohashi S: EBP50, a beta-catenin associating protein, enhances Wnt signaling and is overexpressed in hepatocellular carcinoma. Hepatology. 38:178–186. 2003. View Article : Google Scholar : PubMed/NCBI
20	Fraenzer JT, Pan H, Minimo L Jr, Smith GM, Knauer D and Hung G: Overexpression of the NF2 gene inhibits schwannoma cell proliferation through promoting PDGFR degradation. Int J Oncol. 24:1493–1500. 2003.PubMed/NCBI
21	Stemmer-Rachamimov AO, Wiederhold T, Nielsen GP, et al: NHE-RF, a merlin-interacting protein, is primarily expressed in luminal epithelia, proliferative endometrium, and estrogen receptor-positive breast carcinomas. Am J Pathol. 158:57–62. 2001. View Article : Google Scholar
22	Song J, Bai J, Yang W, Gabrielson EW, Chan DW and Zhang Z: Expression and clinicopathological significance of oestrogen-responsive ezrin-radixin-moesin-binding phosphoprotein 50 in breast cancer. Histopathology. 51:40–53. 2007. View Article : Google Scholar : PubMed/NCBI
23	Georgescu MM, Morales FC, Molina JR and Hayashi Y: Roles of NHERF1/EBP50 in cancer. Curr Mol Med. 8:459–468. 2008. View Article : Google Scholar : PubMed/NCBI
24	Cardone RA, Bagorda A, Bellizzi A, Busco G, Guerra L, Paradiso A, Casavola V, Zaccolo M and Reshkin SJ: Protein kinase A gating of a pseudopodial-located RhoA/ROCK/p38/NHE1 signal module regulates invasion in breast cancer cell lines. Mol Biol Cell. 16:3117–3127. 2005. View Article : Google Scholar : PubMed/NCBI
25	Cardone RA, Bellizzi A, Busco G, Weinman EJ, Dell’Aquila ME, Casavola V, Azzariti A, Mangia A, Paradiso A and Reshkin SJ: The NHERF1 PDZ2 domain regulates PKA-RhoA-p38-mediated NHE1 activation and invasion in breast tumor cells. Mol Biol Cell. 18:1768–1480. 2007. View Article : Google Scholar : PubMed/NCBI
26	Hayashi Y, Molina JR, Hamilton SR and Georgescu MM: NHERF1/EBP50 is a new marker in colorectal cancer. Neoplasia. 12:1013–1022. 2010.PubMed/NCBI
27	Hamilton SR, Vogelstein B, Kudo S, Riboli E, Nakamura S and Hainaut P: Carcinoma of the colon and rectum. WHO Classification of Tumors: Pathology and Genetics of Tumors of Digestive System. Hamilton SR and Aaltonen LA: IARC Press; Lyon, France: pp. 105–119. 2000
28	Goldstein NS and Armin M: Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarcinoma: implications for a standardized scoring system. Cancer. 92:1331–1346. 2001. View Article : Google Scholar
29	Takahashi Y, Morales FC, Kreimann EL and Georgescu MM: PTEN tumor suppressor associates with NHERF proteins to attenuate PDGF receptor signalling. EMBO J. 5:910–920. 2006. View Article : Google Scholar : PubMed/NCBI
30	Kreimann EL, Morales FC, de Orbeta-Cruz J, Takahashi Y, Adams H, Liu TJ, McCrea PD and Georgescu MM: Cortical stabilization of beta-catenin contributes to NHERF1/EBP50 tumor suppressor function. Oncogene. 26:5290–5299. 2007. View Article : Google Scholar : PubMed/NCBI
31	Lazar CS, Cresson CM, Lauffenburger DA and Gill GN: The Na⁺/H⁺ exchanger regulatory factor stabilizes epidermal growth factor receptors at the cell surface. Mol Biol Cell. 15:5470–5480. 2004.
32	Wei Q, Shui Y, Zheng S, Wester K, Nordgren H, Nygren P, Glimelius B and Carlsson J: EGFR, HER2 and HER3 expression in primary colorectal carcinomas and corresponding metastases: implications for targeted radionuclide therapy. Oncol Rep. 25:3–11. 2011.PubMed/NCBI
33	Ljuslinder I, Malmer B, Isaksson-Mettävainio M, Oberg A, Henriksson R, Stenling R and Palmqvist R: ErbB 1–4 expression alterations in primary colorectal cancers and their corresponding metastases. Anticancer Res. 29:1489–1494. 2009.
34	Scartozzi M, Bearzi I, Berardi R, Mandolesi A, Pierantoni C and Cascinu S: Epidermal growth factor receptor (EGFR) downstream signalling pathway in primary colorectal tumours and related metastatic sites: optimising EGFR-targeted treatment options. Br J Cancer. 97:92–97. 2007. View Article : Google Scholar
35	Krasinskas AM: EGFR signaling in colorectal carcinoma. Patholog Res Int. 9329322011.PubMed/NCBI