Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Protein Kinase Inhibitors/therapeutic use , Mutation , ErbB Receptors/genetics , Antineoplastic Agents/therapeutic useABSTRACT
Transforming growth factor beta (TGF-ß) acts as a tumor-suppressing cytokine in healthy tissues and non-malignant tumors. Yet, in malignancy, TGF-ß can exert the opposite effects that can promote proliferation of cancer cells. C-Kit plays a prominent role in stem cell activation and liver regeneration after injury. However, little is known about the cross-talk between TGF-ß and C-Kit and its role in the progression of hepatocellular carcinoma (HCC). Here, we studied the effect of increasing doses of TGF-ß1 on CD44+CD90+ liver stem cells (LSCs) and C-Kit gene expression in malignant and adjacent non-malignant liver tissues excised from 32 HCC patients. The percentage of LSCs in malignant tumors was two times higher compared to their counterparts from the non-malignant tissues. When treated with increasing doses of TGF-ß1, proliferation of both malignant and non-malignant LSCs was progressively suppressed, but low TGF-ß1 dose failed to suppress the growth of malignant LSCs. Moreover, C-Kit exons 9 and 11 were expressed in malignant LSCs, but not in their non-malignant counterparts. Analysis of C-Kit detected mutations in exon 9 (but not in exon 11) in some malignant liver cells resulting in the changes in the amino acid sequence and dysregulation of protein structure and function. Interestingly, in malignant liver cells, mutations in exon 9 were associated with high-viremia hepatitis C virus (HCV), and expression of this exon was not suppressed by the TGF-ß1 treatment at all doses. To our knowledge, this is the first report that mutations in the C-Kit gene in HCC patients are associated with high- viremia HCV. Our study emphasizes the need for investigation of the TGF-ß1 level and C-Kit mutations in patients with chronic HCV for HCC prevention and better therapy management.
Subject(s)
Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Hepacivirus , Hepatitis C, Chronic/genetics , Hepatitis C, Chronic/metabolism , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Proto-Oncogene Proteins c-kit/genetics , Transforming Growth Factor beta1/pharmacology , Aged , Carcinoma, Hepatocellular/etiology , Cell Proliferation/drug effects , Cells, Cultured , Drug Resistance, Multiple, Viral , Exons/genetics , Female , Gene Expression , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/drug therapy , Humans , Hyaluronan Receptors/metabolism , Liver/pathology , Liver Neoplasms/etiology , Male , Middle Aged , Mutation , Neoplastic Stem Cells/metabolism , Thy-1 Antigens/metabolism , ViremiaABSTRACT
BACKGROUND: Lung cancer is known as the top cancer killer in most developed countries. However, there is currently no promising diagnostic or prognostic biomarker for lung cancer. This study aims to discover non-invasive differential markers in the serum of lung cancer patients, to determine the protein identity of the candidate biomarker(s), and to investigate any clinical implication of the biomarker(s) concerned. METHODS: Blood specimens were collected from 154 pre-operative patients with lung cancer and 35 healthy blood donors with no evidence of lung cancer. Fractionated serum samples were processed by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (MS). Candidate biomarker was identified using sodium dodecyl sulphate polyacrylamide gel electrophoresis and tryptic digestion followed by tandem MS fragmentation analysis, which was subsequently validated with immunoassay. RESULTS: A differential protein with m/z 11.6 kDa was detected and identified as an isoform of human serum amyloid A (SAA). It was significantly increased by 1822% in lung cancer patients when compared with the healthy controls, which gave an area under the receiver operator characteristic curve of 0.88. In addition, the protein was also significantly elevated by 77% in lung cancer patients with survival <5 years when compared with patients with survival > or =5 years. CONCLUSION: There are several functions of the SAA protein, described in the context of inflammation, that are compatible with the mechanism of tumour invasion and metastasis. Our study not only detected increased SAA level in the serum of lung cancer patients but also identified that elevated SAA level may be a non-invasive biomarker useful for the prediction of lung cancer prognosis.
