RESUMO
Acquired resistance is a common phenomenon for HCC patients who undergone sorafenib treatment, however the mechanism by which acquired resistance develops remains elusive. In this study, we found that GRP78 could be detected in the serum samples of HCC patients and the conditional medium of multiple HCC cell lines, suggesting that GRP78 is secreted by HCC cells. Further studies showed that secreted GRP78 facilitated the proliferation and inhibited the apoptosis induced by sorafenib both in HCC cell lines and in tumor xenografts. We further found that secreted GRP78 could interact physically with EGFR, therefore activates EGFR signaling pathway. knockdown of EGFR decreased secreted GRP78 induced phosphorylation of SRC and STAT3. By contrast, overexpression of EGFR further enhanced the phosphorylation of SRC and STAT3 induced by secreted GRP78, suggesting the critical role of EGFR in secreted GRP78 conferred resistance to sorafeinib. Moreover, inhibition of SRC by PP2 antagonized the resistance to sorafenib and inhibited the activation of STAT3 conferred by secreted GRP78. Taken together, our results showed that secreted GRP78 could interact with EGFR, activate EGFR-SRC-STAT3 signaling, conferring the resistance to sorafenib.
Assuntos
Carcinoma Hepatocelular/patologia , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/metabolismo , Proteínas de Choque Térmico/metabolismo , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Proliferação de Células/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Niacinamida/farmacologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas pp60(c-src)/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos , Sorafenibe , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To investigate the role of matrix metalloproteinase-7 (MMP-7) expression in caricinogenesis and progression of gastric cancer. METHODS: We studied MMP-7 expression and microvessel density (MVD) in adjacent mucosa and primary foci of 113 cases of gastric cancer by streptavidin-biotin-immunoperoxidase method using anti-MMP-7 and anti-CD34 antibodies. MMP-7 expression and mean MVD were compared with clinicopathological features of gastric cancer, with the relationship between MMP-7 expression and MVD concerned in gastric cancer. RESULTS: MMP-7 showed positive expression in adjacent mucosa of gastric cancer (29.20%, 33/113), less than that in gastric cancer (69.03%, 78/113). MMP-7 expression in primary foci of gastric cancer was positively correlated with tumor size, invasive depth, metastasis and TNM staging (P<0.05), but not with differentiation or growth pattern of gastric cancer (P>0.05). Positive correlation of mean MVD with tumor size, invasive depth, metastasis and TNM staging was found (P<0.05), despite no relationship between mean MVD and differentiation of gastric cancer (P>0.05). Mean MVD was dependent on MMP-7 expression in gastric cancer (P<0.05). CONCLUSION: Upregulated expression of MMP-7 played an important role in carcinogenesis and progression by participating in growth, invasion, metastasis and angiogenesis of gastric cancer. MMP-7 expression could be regarded as an effective and objective marker to reflect the biological behaviors of gastric cancer.
