Abstract
BackgroundHepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Chemotherapy is an alternative treatment for advanced HCCs, but chemo-resistance prevents cancer therapies from achieving stable and complete responses. Understanding the underlying mechanisms in chemo-resistance is critical to improve the efficacy of HCC.MethodsThe expression levels of Id-1 and CCN2 were detected in large cohorts of HCCs, and functional analyses of Id-1 and CCN2 were performed both in vitro and in vivo. cDNA microarrays were performed to evaluate the alterations of expression profiling of HCC cells with overexpression of CCN2. Finally, the role of downstream signaling of MAPK/Id-1 signaling pathway in oxaliplatin resistance were also explored.ResultsThe increased expression of Id-1 and CCN2 were closely related to oxaliplatin resistance in HCC. Upregulation of CCN2 and Id-1 was independently associated with shorter survival and increased recurrence in HCC patients, and significantly enhanced oxaliplatin resistance and promoted lung metastasis in vivo, whereas knock-down of their expression significantly reversed the chemo-resistance and inhibited HCC cell stemness. cDNA microarrays and PCR revealed that Id-1 and MAPK pathway were the downstream signaling of CCN2. CCN2 significantly enhanced oxaliplatin resistance by activating the MAPK/Id-1 signaling pathway, and Id-1 could upregulate CCN2 in a positive feedback manner.ConclusionsCCN2/MAPK/Id-1 loop feedback amplification is involved in oxaliplatin resistance, and the combination of oxaliplatin with inhibitor of CCN2 or MAPK signaling could provide a promising approach to ameliorating oxaliplatin resistance in HCC.
Highlights
Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide
Increased expression of vimentin, CD44, aldehyde dehydrogenase 1 (ALDH1), and epithelial cell adhesion molecule (EpCAM), which are related to epithelial–mesenchymal transition (EMT) and stemness, were upregulated in subcutaneous oxaliplatin-resistant tumors (Supplementary Fig. 1)
The expression levels of Id-1 and CCN2 were investigated in seven HCC cell lines with different malignancy phenotypes of oxaliplatin resistance (IC50: HCC-M3, 32.10 ± 3.28; HCC-97H, 28.98 ± 2.37; PLC, 7.10 ± 1.49; Hep3B, 4.52 ± 0.88; HepG2, 7.01 ± 0.75; Huh7, 3.86 ± 0.58; L02, 5.78 ± 0.32)
Summary
Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Chemotherapy is an alternative treatment for advanced HCCs, but chemo-resistance prevents cancer therapies from achieving stable and complete responses. CDNA microarrays were performed to evaluate the alterations of expression profiling of HCC cells with overexpression of CCN2. Upregulation of CCN2 and Id-1 was independently associated with shorter survival and increased recurrence in HCC patients, and significantly enhanced oxaliplatin resistance and promoted lung metastasis in vivo, whereas knock-down of their expression significantly reversed the chemo-resistance and inhibited HCC cell stemness. CDNA microarrays and PCR revealed that Id-1 and MAPK pathway were the downstream signaling of CCN2. CCN2 significantly enhanced oxaliplatin resistance by activating the MAPK/Id-1 signaling pathway, and Id-1 could upregulate CCN2 in a positive feedback manner. The molecular characterization of chemo-resistant HCC is critical for further improving the efficacy of chemotherapy. In our previous cDNA microarray study of oxaliplatin-resistant HCCs, we have found significant upregulations of 267 genes including CCN2 and Id-1 (inhibitor of DNA binding protein-1) [3], while the accurate role and relationship of which in oxaliplatin resistance is still not yet clear in HCC
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