FMNL1 Exhibits Pro-Metastatic Activity via CXCR2 in Clear Cell Renal Cell Carcinoma

Abstract

Formin-like (FMNL) proteins are responsible for cytoskeletal remodeling and have been implicated in the progression and spread of human cancers. Yet the clinical significance and biological function of FMNL1 in clear cell renal cell carcinoma (ccRCC) remain unclear. In this study, the expression of FMNL1 in ccRCC and its clinical value were determined by tissue microarray-based IHC and statistical analyses. The role of FMNL1 in ccRCC metastasis and the underlying mechanism were investigated via in vitro and in vivo models using gene regulation detection, ChIP, Luciferase reporter assays, and rescue experiments. We show that FMNL1 is upregulated in ccRCC and exhibits pro-metastatic activity via induction of CXCR2. High expression of FMNL1 is significantly correlated with advanced tumor stage, higher pathological tumor grade, tumor metastasis, and unfavorable prognosis in two independent cohorts containing over 800 patients with ccRCC. The upregulation of FMNL1 in ccRCC is mediated by the loss of GATA3. Ectopic expression of FMNL1 promotes, whereas FMNL1 depletion inhibits cell migration in vitro and tumor metastasis in vivo. The FMNL1-enhanced cell mobility is markedly attenuated by the knockdown of CXCR2. Further studies demonstrate that FMNL1 increases the expression of CXCR2 via HDAC1. In clinical samples, FMNL1 expression is positively associated with CXCR2, and is negatively connected to GATA3 expression. Collectively, our data suggest FMNL1 serve as a potential prognostic factor and function as an oncogene. The axis of GATA3/FMNL1/CXCR2 may present a promising therapeutic target for tumor metastasis in ccRCC.

Formins in Human Disease

“…Altered expression of formins affects cell morphology and can promote EMT. Examples are DIAPH3 in hepatocellular carcinoma cells [288]; FMNL1 in non-small cell lung cancer cells [293], clear cell renal cell carcinoma cells [281] and nasopharyngeal carcinoma cells [277]; FMNL2 in gastric cancer cells [312] and colorectal carcinoma cells [262]; FMNL3 in nasopharyngeal carcinoma cells and tumor xenografts [279]; and FHOD1 in lung carcinoma [294].…”

“…Invasion by the mesenchymal mode is facilitated by the formation of invadopodia, which are actin-based protrusions of the plasma membrane that contain metalloproteases, such as MMP2 and MMP9, that degrade the extracellular matrix [319]. DIAPH1-3 regulate invasion in cell cultures, and reduce metastasis and tumor volume in nude mice inoculated with breast cancer [243][244][245] and glioma [230]; FMNL1 does the same in glioblastoma and clear cell renal cell carcinoma cells [236,281]; FMNL2 [263] and FMNL3 [267] in colorectal cancer cells; FMNL3 in nasopharyngeal carcinoma cells [279]; and FHOD1 in oral squamous carcinoma cells [280]. As with the case of DIAPH1-3 [230,243,244], other formins could also control invasion by regulating the efficient formation of invadopodia, and the expression levels, localization and activity of metalloproteases [243].…”

“…These and other studies also examined the relative levels of formin, determined by immunohistochemical analysis of biobank tumor samples relative to paired normal tissue, or levels of formin mRNA, to identify associations with the clinicopathological characteristics of the corresponding patient, such as tumor size, presence of distant metastasis, and outcome. Some examples of strong correlations are DAAM1 in breast cancer [248]; FMNL1 in nasopharyngeal cancer [277], non-small cell lung cancer [293], and clear cell renal cell cancer [281]; and of FMNL3 in colorectal cancer [268].…”

Development and Validation of an IL6/JAK/STAT3-Related Gene Signature to Predict Overall Survival in Clear Cell Renal Cell Carcinoma

“…Besides, Peng et al (2020) claimed that collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8 + T cell exhaustion, similar to Xu et al’s findings ( Xu et al, 2020 ). The reports about FMNL1 extensively focused on its role in aggressiveness of many tumors, such as nasopharyngeal carcinoma, leukemia, and ccRCC ( Favaro et al, 2013 ; Chen et al, 2018 ; Zhang et al, 2020 ), while WDFY4 extensively focused on autoimmune diseases ( Kochi et al, 2018 ; Yuan et al, 2018 ; Zhu et al, 2020 ). Unlike previous genes, the reports about c16 or f54 were limited and still need further investigation.…”

Aproximaciones moleculares para la identificación de nuevos biomarcadores y dianas terapéuticas del cáncer de pulmón no microcítico: células madre tumorales, transición epitelial-mesenquimal y modelos de xenoinjertos derivados de pacientes

“…Las forminas están involucradas en el proceso de polimerización de actina y están vinculadas a la progresión del cáncer y otras enfermedades 347,590,591 . Por otro lado, Ezrina es una proteína implicada en la EMT y metástasis, que conecta el citoesqueleto de actina con la membrana celular 348 .…”