Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and the prognosis of HCC patients, especially those with metastasis, remains extremely poor. This is partly due to unclear molecular mechanisms underlying HCC metastasis. Our previous study indicates that MDM2 Binding Protein (MTBP) suppresses migration and metastasis of HCC cells. However, signaling pathways regulated by MTBP remain unknown. To identify metastasis-associated signaling pathways governed by MTBP, we have performed unbiased luciferase reporter-based signal array analyses and found that MTBP suppresses the activity of the ETS-domain transcription factor Elk-1, a downstream target of Erk1/2 MAP kinases. MTBP also inhibits phosphorylation of Elk-1 and decreases mRNA expression of Elk-1 target genes. Reduced Elk-1 activity is caused by inhibited nuclear translocation of phosphorylated Erk1/2 (p-Erk) by MTBP and subsequent inhibition of Elk-1 phosphorylation. We also reveal that MTBP inhibits the interaction of p-Erk with importin-7/RanBP7 (IPO7), an importin family member which shuttles p-Erk into the nucleus, by binding to IPO7. Moreover, high levels of MTBP in human HCC tissues are correlated with cytoplasmic localization of p-Erk1/2. Our study suggests that MTBP suppresses metastasis, at least partially, by down-modulating the Erk1/2-Elk-1 signaling pathway, thus identifying a novel regulatory mechanism of HCC metastasis by regulating the subcellular localization of p-Erk.
Highlights
Metastasis is the primary cause of the poor prognosis in cancer patients, being responsible for about 90% of deaths of patient with solid tumors [1]
Since MDM2 Binding Protein (MTBP)’s effects on cancer cell migration is independent of the Mouse Double Minute 2 homolog (MDM2)-p53 pathway [6, 7], we performed luciferase assays using mutant p53-carrying Hepatocellular carcinoma (HCC) cells lines, PLC/ PRF/5 (p53R249S) and Huh7 (p53Y220C), and the results were compared between control cells and those overexpressing MTBP
We found that fulllength and F4-MTBP interacted with endogenous IPO7, Figure 2: MTBP inhibits nuclear translocation of phosphorylated Erk1/2. (A and B) Western blotting for Erk1/2 and phosphorylated Erk1/2 at Thr202/Tyr204 (p-extracellular signal-regulated kinase (Erk)) using cytoplasmic and nuclear protein extracts from PLC/PRF/5 (A) and Huh7 (B) cells treated with solvent (-) or 50 ng/ml of EGF (+) for 30 min
Summary
Metastasis is the primary cause of the poor prognosis in cancer patients, being responsible for about 90% of deaths of patient with solid tumors [1]. Migration of cancer cells to distant sites in the body is one of the critical steps for metastasis [2]. Identifying the molecular mechanisms of cancer cell migration and metastasis will significantly help in improvement of prognosis of cancer patients. The 5-year survival rate is extremely poor despite surgical resection. This is mainly due to microvascular invasion and extrahepatic metastasis to lymph nodes, lungs, and bones [3, 4]. Identifying and characterizing critical molecular mediators of metastasis suppression would lead to therapeutic intervention in HCC precision therapy
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