Abstract
Most hepatocellular carcinoma (HCC)-associated mortalities are related to the metastasis of cancer cells. The localization of mRNAs and their products to cell protrusions has been reported to play a crucial role in the metastasis. Our previous findings demonstrated that STAT3 mRNA accumulated in the protrusions of metastatic HCC cells. However, the underlying mechanism and functional significance of this localization of STAT3 mRNA has remained unexplored. Here we show that fragile X mental retardation protein (FMRP) modulates the localization and translation of STAT3 mRNA, accelerating HCC metastasis. The results of molecular analyses reveal that the 3′UTR of STAT3 mRNA is responsible for the localization of STAT3 mRNA to cell protrusions. FMRP is able to interact with the 3′UTR of STAT3 mRNA and facilitates its localization to protrusions. Importantly, FMRP could promote the IL-6-mediated translation of STAT3, and serine 114 of FMRP is identified as a potential phosphorylation site required for IL-6-mediated STAT3 translation. Furthermore, FMRP is highly expressed in HCC tissues and FMRP knockdown efficiently suppresses HCC metastasis in vitro and in vivo. Collectively, our findings provide further insights into the mechanism of HCC metastasis associated with the regulation of STAT3 mRNA localization and translation.
Highlights
Most hepatocellular carcinoma (HCC)-associated mortalities are related to the metastasis of cancer cells
Direct RNA sequencing (DRS) results showed that STAT3 mRNA was remarkably enriched in the cell protrusion fraction[32]
STAT3 mRNA was of particular interest, since it was abundantly accumulated in the cell protrusions
Summary
Most hepatocellular carcinoma (HCC)-associated mortalities are related to the metastasis of cancer cells. We show that fragile X mental retardation protein (FMRP) modulates the localization and translation of STAT3 mRNA, accelerating HCC metastasis. Our findings provide further insights into the mechanism of HCC metastasis associated with the regulation of STAT3 mRNA localization and translation. The localization of mRNAs relies on the presence of a cis-acting element, or a zipcode within the mRNA sequence, which is recognized by an RNA-binding protein[14] Most of these mRNAs encode cytoskeletal proteins and signaling factors located in subcellular compartments and have an important role in the accumulation of the corresponding protein products at the protrusions[15]. Many mRNAs encoding transcription factors and nuclear proteins are present in cell protrusions[11,16], the functional significance of this phenomenon in HCC metastasis remains unclear. The association between FMRP and HCC metastasis still needs further exploration
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