Nagaoka Tomoko, Kitaura Kazutaka, Miyata Yukinaga, Kumagai Kenichi, Kaneda Goro, Kanazawa Hideki, Suzuki Satsuki, Hamada Yoshiki, Suzuki Ryuji
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.
Mol Med Rep. 2016 Apr;13(4):3514-20. doi: 10.3892/mmr.2016.4951. Epub 2016 Mar 1.
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.
本研究采用逆转录定量聚合酶链反应分析方法，调查了122例结直肠癌（CRC）患者中表皮生长因子受体（EGFR）家族的表达谱，该家族由四个跨膜酪氨酸激酶受体及其八个配体组成。比较CRC原发肿瘤组织和配对的相邻正常黏膜（ANM）组织样本发现，与ANM组织相比，CRC组织样本中ErbB3而非ErbB1的mRNA表达水平显著升高。配体的表达水平与其相应受体呈现相反趋势，包括EGF、BTC、AREG、EREG和HB-EGF，与ANM组织相比，这些配体在CRC组织中表达增加，而NRG1和NGR2在CRC组织中表达降低。随后，本研究调查了CRC患者中K-ras突变的频率。发现36.8%（45/122）的病例存在K-ras突变，然而，未观察到K-ras突变与临床病理特征之间存在相关性。在CRC组织中，对野生型和突变型K-ras CRC病例的EGFR家族受体及其配体的表达水平进行了测定。与野生型K-ras病例相比，突变型K-ras病例中ErbB1、ErbB2、ErbB3、BTC、AREG、EREG、NRG1和NRG2的表达水平显著降低。这些结果表明，野生型K-ras的CRC肿瘤发生不仅通过ErbB1介导，还通过ErbB2和ErbB3途径介导。值得注意的是，尽管ErbB2不结合任何ErbB配体，但ErbB2可能通过异二聚体而非同二聚体激活肿瘤发生。因此，本研究结果表明，不仅靶向ErbB1，而且靶向ErbB2和ErbB3的最有效策略是使用单克隆抗体治疗。
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