Downregulation of epidermal growth factor receptor family receptors and ligands in a mutant K-ras group of patients with colorectal cancer

Nagaoka,Tomoko; Kitaura,Kazutaka; Miyata,Yukinaga; Kumagai,Kenichi; Kaneda,Goro; Kanazawa,Hideki; Suzuki,Satsuki; Hamada,Yoshiki; Suzuki,Ryuji

doi:10.3892/mmr.2016.4951

Downregulation of epidermal growth factor receptor family receptors and ligands in a mutant K-ras group of patients with colorectal cancer

Authors:
- Tomoko Nagaoka
- Kazutaka Kitaura
- Yukinaga Miyata
- Kenichi Kumagai
- Goro Kaneda
- Hideki Kanazawa
- Satsuki Suzuki
- Yoshiki Hamada
- Ryuji Suzuki
View Affiliations

Affiliations: Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University, Tsurumi‑ku, Yokohama 230‑8501, Japan, Department of Rheumatology and Clinical Immunology, Clinical Research Center for Rheumatology and Allergy, Sagamihara National Hospital, National Hospital Organization, Sagamihara, Kanagawa 252‑0392, Japan, Department of Surgery, Sagamihara National Hospital, National Hospital Organization, Sagamihara, Kanagawa 252‑0392, Japan, Section of Biological Science, Research Center for Odontology, Nippon Dental University, School of Dentistry, Chiyoda‑ku, Tokyo 102‑0071, Japan
Published online on: March 1, 2016 https://doi.org/10.3892/mmr.2016.4951
Pages: 3514-3520

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

The present study investigated the expression profiles of the epidermal growth factor receptor (EGFR) family, which consists of four transmembrane tyrosine kinase receptors and their eight ligands, in 122 patients with colorectal cancer (CRC) using reverse transcription-quantitative polymerase chain reaction analysis. On comparison of the CRC primary tumor and matched adjacent normal mucosa (ANM) tissue samples, the mRNA expression levels of ErbB3, but not ErbB1, were significantly increased in CRC tissue samples, compared with those in the ANM tissues. The expression levels of the ligands exhibited opposing trends to their corresponding receptors, including EGF, BTC, AREG, EREG and HB‑EGF, which were increased in the CRC tissues, whereas NRG1 and NGR2 were decreased in thee CRC tissues, compared with those in the AMN tissues. Subsequently, the present study investigated the frequency of K-ras mutations in the patients with CRC. The K‑ras mutations were found to be present in 36.8% (45/122) of the cases, however, no correlation was observed between K‑ras mutations and clinicopathological characteristics. In the CRC tissues, the expression levels of the EGFR family receptors and their ligands were determined in wild-type and mutant K-ras CRC cases. The expression levels of ErbB1, ErbB2, ErbB3, BTC, AREG, EREG, NRG1 and NRG2 were significantly decreased in the mutant K‑ras cases, compared with those in the wild‑type K‑ras cases. These results suggested that the tumorigenesis of CRC with wild‑type K‑ras was mediated through, not only ErbB1, but also through the ErbB2 and ErbB3 pathways. Notably, although ErbB2 does not bind any ErbB ligands, ErbB2 may activate tumorigenesis via a heterodimer, rather than a homodimer. Therefore, the results of the present study suggest that the most effective strategy to target not only ErbB1, but also ErbB2 and ErbB3, is the use of monoclonal antibody treatment.

View Figures

View References

1	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
2	Andre N and Schmiegel W: Chemoradiotherapy for colorectal cancer. Gut. 54:1194–1202. 2005. View Article : Google Scholar : PubMed/NCBI
3	Jemal A, Siegel R, Ward E, Hao Y, Xu J and Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 59:225–249. 2009. View Article : Google Scholar : PubMed/NCBI
4	André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, et al: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 350:2343–2351. 2004. View Article : Google Scholar : PubMed/NCBI
5	Carpenter G and Cohen S: Epidermal growth factor. J Biol Chem. 265:7709–7712. 1990.PubMed/NCBI
6	Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, et al: Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: The PRIME study. J Clin Oncol. 28:4697–4705. 2010. View Article : Google Scholar : PubMed/NCBI
7	Lacouture ME, Mitchell EP, Piperdi B, Pillai MV, Shearer H, Iannotti N, Xu F and Yassine M: Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol. 28:1351–1357. 2010. View Article : Google Scholar : PubMed/NCBI
8	Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, et al: Randomized phase III study of panitumumab with fluorouracil, leucovorin and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 28:4706–4713. 2010. View Article : Google Scholar : PubMed/NCBI
9	De Roock W, De Vriendt V, Normanno N, Ciardiello F and Tejpar S: KRAS, BRAF, PIK3CA and PTEN mutations: Implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol. 12:594–603. 2011. View Article : Google Scholar
10	Adjei AA: K-ras as a target for lung cancer therapy. J Thorac Oncol. 3(6 Suppl 2): S160–S163. 2008. View Article : Google Scholar : PubMed/NCBI
11	Messersmith WA and Ahnen DJ: Targeting EGFR in colorectal cancer. N Engl J Med. 359:1834–1836. 2008. View Article : Google Scholar : PubMed/NCBI
12	Sadeghi S, Olevsky O and Hurvitz SA: Profiling and targeting HER2-positive breast cancer using trastuzumab emtansine. Pharmgenomics Pers Med. 7:329–338. 2014.PubMed/NCBI
13	Shak S: Overview of the trastuzumab (Herceptin) anti-HER2 monoclonal antibody clinical program in HER2-overexpressing metastatic breast cancer. Herceptin multinational investigator study group. Semin Oncol. 26(4 Suppl 12): S71–S77. 1999.
14	Aurisicchio L, Marra E, Roscilli G, Mancini R and Ciliberto G: The promise of anti-ErbB3 monoclonals as new cancer therapeutics. Oncotarget. 3:744–758. 2012. View Article : Google Scholar : PubMed/NCBI
15	Mehta SP, Jose P, Mirza A, Pritchard SA, Hayden JD and Grabsch HI: Comparison of the prognostic value of the 6th and 7th editions of the Union for International Cancer Control TNM staging system in patients with lower esophageal cancer undergoing neoadjuvant chemotherapy followed by surgery. Dis Esophagus. 26:182–188. 2013. View Article : Google Scholar
16	Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, et al: The MIQE guidelines: Minimum information for publication of quantitative real-time PCR experiments. Clin Chem. 55:611–622. 2009. View Article : Google Scholar : PubMed/NCBI
17	Caradec J, Sirab N, Keumeugni C, Moutereau S, Chimingqi M, Matar C, Revaud D, Bah M, Manivet P, Conti M and Loric S: 'Desperate house genes': The dramatic example of hypoxia. Br J Cancer. 102:1037–1043. 2010. View Article : Google Scholar : PubMed/NCBI
18	Schmittgen TD and Zakrajsek BA: Effect of experimental treatment on housekeeping gene expression: Validation by real-time, quantitative RT-PCR. J Biochem Biophys Methods. 46:69–81. 2000. View Article : Google Scholar : PubMed/NCBI
19	Lupberger J, Kreuzer KA, Baskaynak G, Peters UR, le Coutre P and Schmidt CA: Quantitative analysis of beta-actin, beta-2-microglobulin and porphobilinogen deaminase mRNA and their comparison as control transcripts for RT-PCR. Mol Cell Probes. 16:25–30. 2002. View Article : Google Scholar : PubMed/NCBI
20	Zhong H and Simons JW: Direct comparison of GAPDH, beta-actin, cyclophilin and 28S rRNA as internal standards for quantifying RNA levels under hypoxia. Biochem Biophys Res Commun. 259:523–526. 1999. View Article : Google Scholar : PubMed/NCBI
21	de Kok JB, Roelofs RW, Giesendorf BA, Pennings JL, Waas ET, Feuth T, Swinkels DW and Span PN: Normalization of gene expression measurements in tumor tissues: Comparison of 13 endogenous control genes. Lab Invest. 85:154–159. 2005. View Article : Google Scholar
22	Biederman J, Yee J and Cortes P: Validation of internal control genes for gene expression analysis in diabetic glomerulosclerosis. Kidney Int. 66:2308–2314. 2004. View Article : Google Scholar : PubMed/NCBI
23	Yarom N and Jonker DJ: The role of the epidermal growth factor receptor in the mechanism and treatment of colorectal cancer. Discov Med. 11:95–105. 2011.PubMed/NCBI
24	Spano JP, Lagorce C, Atlan D, Milano G, Domont J, Benamouzig R, Attar A, Benichou J, Martin A, Morere JF, et al: Impact of EGFR expression on colorectal cancer patient prognosis and survival. Ann Oncol. 16:102–108. 2005. View Article : Google Scholar
25	Lédel F, Hallström M, Ragnhammar P, Öhrling K and Edler D: HER3 expression in patients with primary colorectal cancer and corresponding lymph node metastases related to clinical outcome. Eur J Cancer. 50:656–662. 2014. View Article : Google Scholar
26	Koenders PG, Peters WH, Wobbes T, Beex LV, Nagengast FM and Benraad TJ: Epidermal growth factor receptor levels are lower in carcinomatous than in normal colorectal tissue. Br J Cancer. 65:189–192. 1992. View Article : Google Scholar : PubMed/NCBI
27	Lievre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, Ychou M, Bouché O, Landi B, Louvet C, et al: KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 26:374–379. 2008. View Article : Google Scholar : PubMed/NCBI
28	Andreyev J and Cunningham D: Markers, markers everywhere. Prognosis in colorectal cancer-time for a new approach. J Clin Oncol. 19:286–288. 2001.PubMed/NCBI
29	Brink M, de Goeij AF, Weijenberg MP, Roemen GM, Lentjes MH, Pachen MM, Smits KM, de Bruïne AP, Goldbohm RA and van den Brandt PA: K-ras oncogene mutations in sporadic colorectal cancer in the Netherlands cohort study. Carcinogenesis. 24:703–710. 2003. View Article : Google Scholar : PubMed/NCBI
30	Taback B, Bilchik AJ, Saha S, Nakayama T, Wiese DA, Turner RR, Kuo CT and Hoon DS: Peptide nucleic acid clamp PCR: A novel K-ras mutation detection assay for colorectal cancer microme-tastases in lymph nodes. Int J Cancer. 111:409–414. 2004. View Article : Google Scholar : PubMed/NCBI
31	Yunxia Z, Jun C, Guanshan Z, Yachao L, Xueke Z and Jin L: Mutations in epidermal growth factor receptor and K-ras in Chinese patients with colorectal cancer. BMC Med Genet. 11:342010. View Article : Google Scholar : PubMed/NCBI
32	Bazan V, Migliavacca M, Zanna I, Tubiolo C, Grassi N, Latteri MA, La Farina M, Albanese I, Dardanoni G, Salerno S, et al: Specific codon 13 K-ras mutations are predictive of clinical outcome in colorectal cancer patients, whereas codon 12 K-ras mutations are associated with mucinous histotype. Ann Oncol. 13:1438–1446. 2002. View Article : Google Scholar : PubMed/NCBI
33	Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, Ratzkin BJ and Yarden Y: A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol. 16:5276–5287. 1996. View Article : Google Scholar : PubMed/NCBI
34	Pinkas-Kramarski R, Soussan L, Waterman H, Levkowitz G, Alroy I, Klapper L, Lavi S, Seger R, Ratzkin BJ, Sela M and Yarden Y: Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. Embo J. 15:2452–2467. 1996.PubMed/NCBI
35	Lee D, Yu M, Lee E, Kim H, Yang Y, Kim K, Pannicia C, Kurie JM and Threadgill DW: Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium. J Clin Invest. 119:2702–2713. 2009. View Article : Google Scholar : PubMed/NCBI
36	Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW Jr and Leahy DJ: Structure of the extracellular region of HER2 alone and in complex with the herceptin fab. Nature. 421:756–760. 2003. View Article : Google Scholar : PubMed/NCBI