Fragile X mental retardation protein in intrahepatic cholangiocarcinoma: regulating the cancer cell behavior plasticity at the leading edge

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is a rare malignancy of the intrahepatic biliary tract with a very poor prognosis. Although some clinicopathological parameters can be prognostic factors for iCCA, the molecular prognostic markers and potential mechanisms of iCCA have not been well investigated. Here, we report that the Fragile X mental retardation protein (FMRP), a RNA binding protein functionally absent in patients with the Fragile X syndrome (FXS) and also involved in several types of cancers, is overexpressed in human iCCA and its expression is significantly increased in iCCA metastatic tissues. The silencing of FMRP in metastatic iCCA cell lines affects cell migration and invasion, suggesting a role of FMRP in iCCA progression. Moreover, we show evidence that FMRP is localized at the invasive front of human iCCA neoplastic nests and in pseudopodia and invadopodia protrusions of migrating and invading iCCA cancer cells. Here FMRP binds several mRNAs encoding key proteins involved in the formation and/or function of these protrusions. In particular, we find that FMRP binds to and regulates the expression of Cortactin, a critical regulator of invadopodia formation. Altogether, our findings suggest that FMRP could promote cell invasiveness modulating membrane plasticity and invadopodia formation at the leading edges of invading iCCA cells.

FMRP modulates the Wnt signalling pathway in glioblastoma

“…Mice transplanted with shFMR1 GSCs survived significantly longer compared to controls due to reduced cell proliferation and tumor angiogenesis. These findings are consistent with a role of FMRP in tumor cell aggressiveness regulation, as previously described in other cancer types [15,16,18,39].…”

“…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/).…”

Intercepting IRE1 kinase‐FMRP signaling prevents atherosclerosis progression

“…We also transfected wild type BMDMs with either Fmr1‐specific or control siRNA and followed by loading the cells with 3,3′‐dioctadecylindocarbocyanine (dil)‐labeled acetylated LDL (Ac‐LDL) (Carotti et al , 2021 ). Flow cytometry analysis revealed that Fmr1 silencing significantly reduced % dil‐acLDL internalized in macrophages (Fig 2C , Appendix Fig S2A ).…”

M6A-modified circRBM33 promotes prostate cancer progression via PDHA1-mediated mitochondrial respiration regulation and presents a potential target for ARSI therapy

“…Conversely, HNF4α transactivated lncRNA BC200 to form a positive feedback loop, thereby promoting tumour growth and metastasis in invasive mucinous lung adenocarcinoma [37]. Additionally, Carotti et al also found that FMR1 was upregulated in intrahepatic cholangiocarcinoma, bound to Cortactin (a marker of mature invadopodia) mRNA to mediate its expression, and then promoted cell migration and invasiveness by regulating invadopodia formation [38]. Consistently, our results showed that silencing of FMR1 inhibited cell growth and invasion in PCa cells as well.…”