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FMRP regulates STAT3 mRNA localization to cellular protrusions and local translation to promote hepatocellular carcinoma metastasis.

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.

SUBMITTER: Shen Z

PROVIDER: S-EPMC8110961 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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FMRP regulates STAT3 mRNA localization to cellular protrusions and local translation to promote hepatocellular carcinoma metastasis.

Shen Zhifa Z Liu Bowen B Wu Biting B Zhou Hongyin H Wang Xiangyun X Cao Jinling J Jiang Min M Zhou Yingying Y Guo Feixia F Xue Chang C Wu Zai-Sheng ZS

Communications biology 20210510 1

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 retar ...[more]

PMID: 33972660

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Project description:BackgroundIt is well-established that most Hepatocellular carcinoma (HCC) patients die of metastasis, yet the potential mechanisms orchestrating metastasis remain poorly understood. Current evidence suggests that the dysregulation of METTL3-mediated m6A methylation modification is closely associated with cancer progression. STAT3 is an oncogenic transcription factor that reportedly plays a central role in the occurrence and development of HCC. However, the relationship between METTL3 and STAT3 in HCC metastasis remains unclear.MethodsThe relationship between METTL3 expression and the survival of HCC patients was assessed by online tools GEPIA and Kaplan-Meier Plotter. Western blotting, Tissue microarray (TMA), and immunohistochemistry (IHC) staining were used to evaluate the expression levels of METTL3 and STAT3 in HCC cell lines and metastatic and non-metastatic tissues. Methylated RNA immunoprecipitation (MeRIP), MeRIP sequencing (MeRIP-seq), qRT-PCR, RNA immunoprecipitation (RIP), Western blotting and luciferase reporter gene assay were utilized to clarify the mechanism of METTL3 regulating STAT3 expression. Immunofluorescence staining, Western blotting, qRT-PCR, Co-immunoprecipitation (Co-IP), IHC staining, TMA and Chromatin immunoprecipitation (ChIP) assay were performed to explore the mechanism of STAT3 modulating METTL3 localization. Cell viability, wound healing and transwell assay, and orthotopic xenograft model were used to evaluate the role of METTL3-STAT3 feedback loop in the promotion of HCC metastasis in vitro and in vivo.ResultsMETTL3 and STAT3 are both abundantly expressed in high-metastatic HCC cells and tissues. Moreover, a positive correlation was found between the expression of STAT3 and METTL3 in HCC tissues. Mechanistically, METTL3 could induce the m6A modification of STAT3 mRNA, and then promote the translation of m6A-contained STAT3 mRNA by interacting with the translation initiation machinery. In contrast, STAT3 promoted nuclear localization of METTL3 via transcriptionally upregulating WTAP, a vital member of the methyltransferase complex, and facilitated the methyltransferase function of METTL3. METTL3 and STAT3 form a positive feedback loop to accelerate HCC metastasis in vitro and in vivo.ConclusionsOur findings reveal a novel mechanism of HCC metastasis and uncover the METTL3-STAT3 feedback signaling as a potential target for the anti-metastatic treatment of HCC. Video Abstract.

Dataset Information

FMRP regulates STAT3 mRNA localization to cellular protrusions and local translation to promote hepatocellular carcinoma metastasis.

Publications

FMRP regulates STAT3 mRNA localization to cellular protrusions and local translation to promote hepatocellular carcinoma metastasis.

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