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

Abstract

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.

Promising Therapeutic Efficacy of GC1118, an Anti-EGFR Antibody, against KRAS Mutation-Driven Colorectal Cancer Patient-Derived Xenografts

“…The total expression level of each EGFR ligand (nM) did not show any significant association with KRAS mutations as evaluated by ELISA (Table S1 and Figure S2). Notably, consistent with previous reports [30,31], we found that KRAS -mutant PDXs tended to show significantly higher fractions of high-affinity EGFR ligands and lower fractions of low-affinity EGFR ligands (Figure 2A,B), in addition to a higher ratio of high- to low-affinity EGFR ligands, than did the KRAS wild-type PDXs (Figure 2C,D). This indicates that the distribution of high- and low-affinity EGFR ligands depends on the presence of a KRAS mutation.…”

“…Low expression levels of AREG and EREG associated with KRAS mutations might indicate a tumor that is less dependent on EGFR and is therefore particularly prone to developing resistance to anti-EGFR MoAbs [6,8,10,20,21]. Moreover, the expression levels of AREG and EREG were found to be significantly decreased in mutant- KRAS cases, compared to those in the wild-type cases [30]. Sustained extracellular signal–regulated kinases (ERK) signaling mediated by KRAS mutations was shown to boost secretion of the high-affinity EGFR ligands HB-EGF and TGF-α, which in turn activated EGFR in an autocrine fashion [31].…”

The prognostic value of p53 positive in colorectal cancer: A retrospective cohort study

“…The tumor heterogeneity is partially determined by the differences in biomarkers. In this study, we only studied p53 as one possible microscopical prognostic marker which could be considered as a limitation of this study, but the incidence of other biological marker abnormalities, including K-ras, 25 BRAF, 26 DNA mismatch repair (MMR), 27 changed much less than p53. Furthermore, we excluded several macroscopical factors that would have influenced results, and we had a longer median follow-up.…”

Circulating Tumor Cell-Free DNA Genes as Prognostic Gene Signature for Platinum Resistant Ovarian Cancer Diagnosis

“… 53 NRG2 ligand binds with ErbB2 receptors and downstream signaling lead to colorectal cancer and breast cancer progression. 54 , 55 Potential role of Keratin 5 (KRT5) as well as Collagen, type IV, alpha 3 (COL4A3) in invasive metastasis and disease recurrence in ovarian cancer have also been previously known. 56 , 57 Although a defined role for PANX1 in ovarian cancer is thus far unknown, it is shown to promote invasive migration in hepatocellular carcinoma.…”