Abstract
Epidermal growth factor receptor (EGFR) is frequently aberrantly expressed in cancer, and abnormal signalling downstream of this receptor contributes to tumour growth. EGFR variant III (EGFRvIII) is the most commonly altered form of EGFR and contains a truncated ligand-binding domain. Aberrant signalling downstream of this receptor contributes to tumour invasion. We previously reported that EGFRvIII can promote hepatocellular carcinoma (HCC) invasion. However, little is known concerning the mechanisms underlying EGFRvIII-mediated increases in cell motility and invasion in HCC. In this study, we observed that S100A11 was significantly upregulated in Huh-7 cells that overexpressed EGFRvIII. Moreover, S100A11 expression was elevated in HCC tissue samples (68.6%; 35/51), and this elevation was correlated with EGFRvIII expression (p = 0.0020; n = 20). Furthermore, the overexpression of S100A11 can promote HCC cell invasiveness, whereas siRNA against S100A11 can suppress the invasiveness of HCC cells stably transfected with EGFRvIII. Additionally, STAT3 inhibitors can block S100A11 expression and S100A11 promoter activity in HCC cells with stable overexpression of EGFRvIII. Furthermore, mutation in STATx binding sites could abolish the S1000A11 promoter activity stimulation by EGFRvIII. Taken together, the results demonstrate that the EGFRvIII-STAT3 pathway promotes cell migration and invasion by upregulating S100A11.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer mortality worldwide
The five differentially expressed protein spots were further analysed by LC-mass spectrometry (MS)/MS, and five candidate molecules were identified: S100 calcium binding protein A11 (S100A11), peroxiredoxin 1 (PRDX1), tropomyosin 3 isoform 2, nucleophosmin1 isoform 2, and cofilin-1
Metastasis remains a major challenge in the treatment of patients with HCC
Summary
HCC is the sixth most common cancer and the third most common cause of cancer mortality worldwide. Hepatocellular carcinoma (HCC) is a highly aggressive tumour that is rapidly fatal [1]. This type of cancer is usually diagnosed at a stage when the disease is already advanced and incurable. Tumour recurrence after a curative liver resection is high, surgery is the most effective treatment for HCC [2,3]. Due to its important contributions to tumour cell survival, proliferation, and motility, EGFR has been associated with many human malignancies, such as breast cancer, lung cancer, brain cancer, prostate cancer, and liver cancer[4,5,6,7,8,9,10]. The overexpression, deletion, and mutation of the EGFR gene are the most common mechanisms by which EGFR exerts its influence on tumourigenesis[11,12,13]
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