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

Liu, Bowen; Wu, Biting; Zhou, Hongyin; Wang, Xiangyun; Cao, Ji; Jiang, Min; Zhou, Yingying; Guo, Feixia; Xue, Chang; Wu, Zai‐Sheng

doi:10.1038/s42003-021-02071-8

Cited by 12 publications

(7 citation statements)

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“…1 A, B), suggesting the potential role of METTL3 on HCC progression. STAT3 is a classic oncogene that plays a crucial role in promoting the proliferation and metastasis of cancer cells [ 19 , 26 , 27 ]. In a previous study, we revealed the pro-metastatic effect of STAT3 on HCC cells [ 19 ].…”

Section: Resultsmentioning

confidence: 99%

“…STAT3 is a classic oncogene that plays a crucial role in promoting the proliferation and metastasis of cancer cells [ 19 , 26 , 27 ]. In a previous study, we revealed the pro-metastatic effect of STAT3 on HCC cells [ 19 ]. Thus, we wondered if there was a potential relationship between METTL3 and STAT3 in the promotion of HCC metastasis.…”

Section: Resultsmentioning

confidence: 99%

“…Among these family members, STAT3 is an important oncogene that has been widely studied in recent years. A growing number of studies substantiate that STAT3 can affect the survival, proliferation, angiogenesis, and metastasis of cancer cells via regulating the expression of different genes, thereby promoting the malignant development of cancer [ 17 – 19 ]. One study revealed that high expression of STAT3 in HCC has been closely associated with poor prognosis [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

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METTL3 and STAT3 form a positive feedback loop to promote cell metastasis in hepatocellular carcinoma

Liu

Cao

et al. 2023

Cell Commun Signal

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Background It 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. Methods The 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. Results METTL3 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. Conclusions Our 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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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METTL3 and STAT3 form a positive feedback loop to promote cell metastasis in hepatocellular carcinoma

Liu

Cao

et al. 2023

Cell Commun Signal

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“…RNA-binding proteins (RBPs) are emerging as key regulators in cancer development, playing a key role in posttranscriptional control and gene expression homeostasis [14]. In this scenario, growing evidence shows the overexpression of the RBP Fragile X Mental Retardation Protein (FMRP) in several kinds of tumors, regulating cancer progression and invasiveness [15][16][17][18]. The FMR1 gene, encoding FMRP, is expressed in different tissues and cancer cell types (https://www.genevestigator.com/gv/).…”

Section: Introductionmentioning

confidence: 99%

FMRP modulates the Wnt signalling pathway in glioblastoma

et al. 2022

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Converging evidence indicates that the Fragile X Messenger Ribonucleoprotein (FMRP), which absent or mutated in Fragile X Syndrome (FXS), plays a role in many types of cancers. However, while FMRP roles in brain development and function have been extensively studied, its involvement in the biology of brain tumors remains largely unexplored. Here we show, in human glioblastoma (GBM) biopsies, that increased expression of FMRP directly correlates with a worse patient outcome. In contrast, reductions in FMRP correlate with a diminished tumor growth and proliferation of human GBM stem-like cells (GSCs) in vitro in a cell culture model and in vivo in mouse brain GSC xenografts. Consistently, increased FMRP levels promote GSC proliferation. To characterize the mechanism(s) by which FMRP regulates GSC proliferation, we performed GSC transcriptome analyses in GSCs expressing high levels of FMRP, and in these GSCs after knockdown of FMRP. We show that the WNT signalling is the most significantly enriched among the published FMRP target genes and genes involved in ASD. Consistently, we find that reductions in FMRP downregulate both the canonical WNT/β-Catenin and the non-canonical WNT-ERK1/2 signalling pathways, reducing the stability of several key transcription factors (i.e. β-Catenin, CREB and ETS1) previously implicated in the modulation of malignant features of glioma cells. Our findings support a key role for FMRP in GBM cancer progression, acting via regulation of WNT signalling.

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“…Initially, the relationship between FMRP and cancer was identified due to the observation that patients with Fragile X Syndrome (FXS) have a decreased risk of cancer [ 19 ]. Subsequently, studies revealed that FMRP is overexpressed in hepatocellular carcinoma and breast cancer and participates in regulation of the tumor metastasis phenotype [ 20 , 21 ]. RAS-related C3 botulinum toxin substrate 1 (RAC1) is a core member of the Rho subfamily in the Ras superfamily and is involved in the biological processes of cell migration, invasion and adhesion [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

FMRP ligand circZNF609 destabilizes RAC1 mRNA to reduce metastasis in acral melanoma and cutaneous melanoma

Shang

et al. 2022

J Exp Clin Cancer Res

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Background Melanoma is a type of malignant tumor with high aggressiveness and poor prognosis. At present, metastasis of melanoma is still an important cause of death in melanoma patients. However, the potential functions and molecular mechanisms of most circular RNAs (circRNAs) in melanoma metastasis remain unknown. Methods circRNAs dysregulated in melanoma cell subgroups with different metastatic abilities according to a screening model based on repeated Transwell assays were identified with a circRNA array. The expression and prognostic significance of circZNF609 in skin cutaneous melanoma and acral melanoma cells and tissues were determined by qRT–PCR, nucleoplasmic separation assays and fluorescence in situ hybridization. In vitro wound healing, Transwell and 3D invasion assays were used to analyse melanoma cell metastasis ability. Tail vein injection and intrasplenic injection were used to study in vivo lung metastasis and liver metastasis, respectively. The mechanism of circZNF609 was further evaluated via RNA immunoprecipitation, RNA pull-down, silver staining, and immunofluorescence colocalization assays. Results circZNF609 was stably expressed at low levels in melanoma tissues and cells and was negatively correlated with Breslow depth, clinical stage and prognosis of melanoma patients. circZNF609 inhibited metastasis of acral and cutaneous melanoma in vivo and in vitro. Mechanistically, circZNF609 promoted the binding of FMRP protein and RAC1 mRNA, thereby enhancing the inhibitory effect of FMRP protein on the stability of RAC1 mRNA and ultimately inhibiting melanoma metastasis. Conclusions Our findings revealed that circZNF609 plays a vital role in the metastasis of acral and cutaneous melanoma through the circRNF609-FMRP-RAC1 axis and indicated that circZNF609 regulates the stability of RAC1 mRNA by combining with FMRP, which might provide insight into melanoma pathogenesis and a new potential target for treatment of melanoma.

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

Cited by 12 publications

References 58 publications

METTL3 and STAT3 form a positive feedback loop to promote cell metastasis in hepatocellular carcinoma

METTL3 and STAT3 form a positive feedback loop to promote cell metastasis in hepatocellular carcinoma

FMRP modulates the Wnt signalling pathway in glioblastoma

FMRP ligand circZNF609 destabilizes RAC1 mRNA to reduce metastasis in acral melanoma and cutaneous melanoma

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