Phenotype of vigilin expressing breast cancer cells binding to the 69 nt 3′UTR element in CSF-1R mRNA

Abstract

Vigilin, a nucleocytoplasmic shuttling protein, post-transcriptionally suppresses proto-oncogene c-fms expression (encoding CSF-1R) in breast cancer by binding to a 69 nt cis-acting 3-UTR element in CSF-1R mRNA. CSF-1R is an important mediator of breast cancer development, metastasis, and survival. We confirm that vigilin decreases in vitro reporter luciferase activity as well as the translation rate of target mRNAs. We further explore the mechanism of suppression of CSF-1R. We show that the 69 nt binding element has profound effects on translation efficiency of CSF-1R mRNA, not seen in the presence of mutation of the element. Also, mutation of the 69 nt element in the CSF-1R mRNA 3′UTR both interferes with direct vigilin binding and obviates effect of vigilin overexpression on translational repression of CSF-1R. We show that stable vigilin binding requires the full length 69 nt CSF-1R element, including the 26 nt pyrimidine-rich core. Furthermore, titration of endogenous vigilin and other proteins which bind the 69 nt element, by exogenously introduced CSF-1R mRNA 3′UTR containing the pyrimidine-rich sequence, increases the adhesion, motility, and invasion of breast cancer cells. This phenotypic effect is not seen when the 69 nt element is deleted. Lastly, we are the first to show that human breast tissues exhibit strong vigilin expression in normal breast epithelium. Our pilot data suggest decreased vigilin protein expression, along with shift from the nucleus to the cytoplasmic location, in the transition to ductal carcinoma in situ.

The TSC Complex-mTORC1 Axis: From Lysosomes to Stress Granules and Back

“…Like the G3BPs, also HDLBP (Yang et al, 2014) and PI(3,5)P2 (Hou et al, 2019;Ikonomov et al, 2019) control proliferation and migration of cancer cells. In agreement, altered HDLBP levels have been reported in different tumor entities (Yang et al, 2014;Woo et al, 2019), and PI(3,5)P2 and the G3BPs have been linked to malignancies and neuronal disorders (Wallroth and Haucke, 2018;Mandal, 2020;Prentzell et al, 2021). These disorders may arise, at least in part, from aberrant lysosomal TSC complex levels and mTORC1 activity.…”

RhoA and vigilin are candidates for immunohistochemical markers for epithelioid malignant mesothelioma

“…Vigilin was diffusely positive in the cytoplasm, consistent with its localisation in the ER. We hypothesise that the high IHC stainability of calretinin and vigilin may indicate that ER stress in MM 28 promotes the accumulation of vigilin 17 . The ER also functions as an intracellular calcium reservoir and is a calcium-mediated signal transmission site.…”

“…Also, vigilin may promote hepatocellular carcinoma cell proliferation and tumour growth 29 . Besides, vigilin is downregulated in breast cancer cells and is known to downregulate the post-transcriptional expression of the proto-oncogene c-fms encoding CSF-1R in breast cancer 17 . However, it remains unclear whether vigilin is directly involved in the tumorigenesis of epithelioid MM.…”

“…Second, we noted vigilin protein, an RNA-binding nuclear-cytoplasmic shuttle protein that is localised to the nucleus and the rough ER. This protein plays a vital role in cellular sterol metabolism 17 and is one of the candidate markers of lung small cell carcinoma 18 . ER stress has been noted as one of the pathogenic factors of MM 19 .…”

Association of mammographic density with blood DNA methylation

“…The top intragenic DMPs by p-value were located within the HDLBP, TGFB2, CCT4 , and PAX8 genes. HDLBP codes for the protein vigilin, which is strongly expressed in normal breast epithelium [ 71 ] and is a candidate tumour suppressor [ 72 ] that has been shown to impair proliferation of breast cancer cells in vitro [ 73 ]. TGFB2 encodes an isoform of TGF-β, a key regulator of cell development and proliferation with both tumour-suppressor and oncogenic functions [ 74 ], including in breast cancer [ 75 ].…”