Zebrafish Minichromosome Maintenance Protein 5 Gene Regulates the Development and Migration of Facial Motor Neurons via Fibroblast Growth Factor Signaling.

Minichromosome maintenance protein 5 (MCM5), a member of the microchromosomal maintenance protein family, plays an important role in the initiation and extension of DNA replication. However, its role in neural development in zebrafish remains unclear. Here, we used morpholino (MO) and CRISPR/Cas9 to knock down mcm5 and investigated the developmental features of facial motor neurons (FMNs) in the hindbrain of zebrafish. We found that knockdown of mcm5 using mcm5 MO resulted in a small head, small eyes, and a blurred midbrain-hindbrain boundary, while MO injection of mcm5 led to decrease in FMNs and their migration disorder. However, the mutant of mcm5 only resulted in the migration defect of FMNs rather than quantity change. We further investigated the underlying mechanism of mcm5 in the development of hindbrain using in situ hybridization (ISH) and fgfr1a mRNA co-injected with mcm5 MO. Results from ISH showed that the fibroblast growth factor (FGF) signaling pathway was changed when the MCM5 function was lost, with the decrease in fgfr1a and the increase in fgf8, while that of pea3 had opposite trend. FMN development defects were rescued by fgfr1a mRNA co-injected with mcm5 MO. Our results demonstrated that FGF signaling pathway is required for FMN development in zebrafish. Specifically, mcm5 regulates FMN development during zebrafish growing.

Targeted inhibition of FGF19/FGFR cascade improves antitumor immunity and response rate in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common liver cancer globally, claiming nearly 1 million lives each year. The overexpression of fibroblast growth factor (FGF) receptors (FGFRs) signaling cascade has been shown to contribute to tumorigenesis, metastasis, and poor prognosis in HCC. Therefore, targeted inhibition of the FGF/FGFR cascade may represent a new treatment strategy for HCC patients. METHODS: HCC patient-derived xenograft (PDX) models were implanted into either severe combined immunodeficient (SCID) or CD34+hu-NSG (humanized) mice and subsequently treated with vehicle, infigratinib (FGFR1-3 inhibitor), FGF401 (FGFR4 inhibitor), or the combination of infigratinib and FGF401. Tumor progressions, overall survival of mice, lung metastasis, and drug resistance were monitored, and samples collected at the end of the treatment cycle were subjected to Western blot analyses and immunohistochemistry. RESULTS: HCC PDX models expressing high levels of FGF19/FGFR4 or FGFR2/3 showed favorable initial treatment response to FGF401 and infigratinib, respectively. However, progressive disease due to acquired resistance was observed. Combination infigratinib/FGF401 augmented the antitumor activity, response rate, and overall survival of mice. This combination significantly increased the infiltration of B cells, macrophages, CD8+ T cells, and CD4+ T cells associated with granzyme-B-mediated apoptosis, delayed onset of resistance, and inhibited metastasis by potently inhibiting several critical signaling pathways involved in proliferation and metastasis. CONCLUSIONS: Our findings suggest that HCC patients with high FGFR2/3 or FGF19/FGFR4 expressing tumors might benefit from a combination infigratinib/FGF401; thus, supporting its evaluation in clinical trials.

miR-628 reduces prostate cancer proliferation and invasion via the FGFR2 signaling pathway.

Recently, microRNA (miR)-628 was identified as a potential biomarker for several types of cancer, including prostate cancer (PCa). The aim of the present study was to investigate miR-628 expression and its underlying mechanism in PCa cell proliferation and invasion and the fibroblast growth factor receptor 2 (FGFR2) signaling pathway. The serum expression levels of miR-628, prostate-specific antigen, fibroblast growth factor 1, and FGFR2 were examined in patients with PCa. The relative expression levels of miR-628 and FGFR2 were determined by reverse transcription-quantitative polymerase chain reaction in PCa cells following transfection with miR-628-5p mimic or inhibitor. In addition, the protein expression level of FGFR2 was examined by western blot analysis following transfection with miR-628-5p mimic or inhibitor. Following bioinformatics analysis, dual-luciferase reporter assay was used to confirm the direct interaction between miR-628 and FGFR2. The current study demonstrated that the protein expression level of FGFR2 decreased following transfection with miR-628-5p mimic and increased following transfection with miR-628-5p inhibitor. Similarly, the proliferation and invasion of PCa cells were significantly enhanced following transfection with miR-628-5p inhibitor. By contrast, the proliferation and invasion of PCa cells were significantly inhibited following transfection with miR-628 mimic. Therefore, downregulating the expression level of miR-628 may increase the expression level of FGF in PCa, thereby promoting tumor proliferation and invasion. In conclusion, the FGF signaling pathway may be involved in promoting PCa cell proliferation and invasion. miR-628 may be a potential therapeutic target for patients with PCa.