ArticleBMC cancer2014
Localization of phosphorylated ErbB1-4 and heregulin in colorectal cancer.
Article in BMC cancer, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 19 citations in OpenAlex.
- Genetic analysis of Japanese patients with small bowel adenocarcinoma using next-generation sequencing.BMC cancer · 2022Article
- The Yin and Yang of ERBB4: Tumor Suppressor and Oncoprotein.Pharmacological reviews · 2022Review
- The role of ErbB4 in cancer.Cellular oncology (Dordrecht, Netherlands) · 2020Review
- Erbb4 Is Required for Cerebellar Developmentand Malignant Phenotype of Medulloblastoma.Cancers · 2020Article
- HER4 promotes the progression of colorectal cancer by promoting epithelial‑mesenchymal transition.Molecular medicine reports · 2020Article
- Clinical significance of overexpression of NRG1 and its receptors, HER3 and HER4, in gastric cancer patients.Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association · 2018Article
- Dual targeting of HER3 and MEK may overcome HER3-dependent drug-resistance of colon cancers.Oncotarget · 2017Article
- A comprehensive review of heregulins, HER3, and HER4 as potential therapeutic targets in cancer.Oncotarget · 2017Review
- Inhibition of Wnt/β-Catenin pathway and Histone acetyltransferase activity by Rimonabant: a therapeutic target for colon cancer.Scientific reports · 2017Article
- The ErbB3 receptor tyrosine kinase negatively regulates Paneth cells by PI3K-dependent suppression of Atoh1.Cell death and differentiation · 2017Article
- Neuregulin expression in solid tumors: prognostic value and predictive role to anti-HER3 therapies.Oncotarget · 2016Article
- Article
- ERBB4 is over-expressed in human colon cancer and enhances cellular transformation.Carcinogenesis · 2015Article
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8 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
backgroundThe ErbB family consists of four proteins including (EGFR)/ErbB1, ErbB2, ErbB3, and ErbB4, and plays a crucial role in the promotion of multiple tumorigenic processes. In addition to the traditional pathways of EGFR signaling, EGFR translocates to the nucleus and acts as a transcription factor in the proliferation of cancer cells. Heregulin is known as both an ErbB3 and an ErbB4 ligand. This study aimed to investigate the expression of heregulin and its relevant EGFR family members as well as their phosphorylated forms in human colorectal cancer (CRC) tissues and to determine the relationship between their expression and clinicopathological factors including patient prognosis.
methodsWe analyzed the effects of exogenous heregulin on ErbB2, ErbB3 and ErbB4 phosphorylation in Caco-2, DLD-1, and HCT 116 colon cancer cell lines by western blot analysis. We examined 155 surgical resections from colorectomy patients. Cellular localization of ErbB1-4, their phosphorylated forms and heregulin protein was analyzed in CRC surgical resections by immunohistochemical analysis. Immunohistochemical results were compared with clinicopathological factors and patient prognosis.
resultsPhosphorylated ErbB2 (pErbB2) and phosphorylated ErbB3 (pErbB3) were detected in both nuclear and cytosolic fractions of Caco-2 and DLD-1 cells stimulated by exogenous heregulin. Whereas, phosphorylated ErbB4 (pErbB4) was detected only in cytosolic fractions of HCT 116 cells stimulated by exogenous heregulin. Phosphorylated EGFR (pEGFR) immunoreactivity was observed in the cytoplasm and nuclei of cancer cells, whereas the pattern of EGFR staining was membranous and cytoplasmic. Subcellular localization of pErbB2, cytoplasmic, membranous, or nuclear, varied among cases. pErbB3 immunoreactivity was exclusively observed in the nuclei of cancer cells. pErbB4 immunoreactivity was observed in the cell membrane of cancer cells. Statistically, heregulin immunoreactivity correlated with pErbB2 and pErbB4 expression. In multivariate analysis for disease free survival, lymph node status, pErbB3 and pErbB4 expression retained independent prognostic significance. In multivariate analysis for overall survival, lymph node status, pEGFR and pErbB4 retained independent prognostic significance.
conclusionsErbB2 and ErbB3 phosphorylated by heregulin localized in the nucleus of CRC cells. Phosphorylated ErbB1-4 and heregulin contribute to poorer patient prognosis in CRC. This heregulin-ErbB family member autocrine loop may be a candidate for targeted treatment of CRC.
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