Abstract
Pancreatic cancer cells express high levels of MUC1, MUC4 and MUC16 mRNAs that encode membrane-bound mucins. These mRNAs share unusual features such as a long half-life. However, it remains unknown how mucin mRNA stability is regulated. Galectin-3 (Gal-3) is an endogenous lectin playing important biological functions in epithelial cells. Gal-3 is encoded by LGALS3 which is up-regulated in pancreatic cancer. Despite the absence of a RNA-recognition motif, Gal-3 interacts indirectly with pre-mRNAs in the nucleus and promotes constitutive splicing. However a broader role of Gal-3 in mRNA fate is unexplored. We report herein that Gal-3 increases MUC4 mRNA stability through an intermediate, hnRNP-L which binds to a conserved CA repeat element in the 3′UTR in a Gal-3 dependent manner and also controls Muc4 mRNA levels in epithelial tissues of Gal3−/− mice. Gal-3 interacts with hnRNP-L in the cytoplasm, especially during cell mitosis, but only partly associates with protein markers of P-Bodies or Stress Granules. By RNA-IP plus RNA-seq analysis and imaging, we demonstrate that Gal-3 binds to mature spliced MUC4 mRNA in the perinuclear region, probably in hnRNP-L-containing RNA granules. Our findings highlight a new role for Gal-3 as a non-classic RNA-binding protein that regulates MUC4 mRNA post-transcriptionally.
Highlights
Galectin-3 (Gal-3), which is a soluble β-galactoside-binding lectin encoded by LGALS3, shuttles from the nucleus to the cytosol, and is secreted in the extracellular milieu by a non-classical secretory pathway[1,2]
room temperature (RT)-qPCR analysis showed that Sh1 cells expressed lower levels of MUC1 and MUC4 mRNAs than the control Sc cells whereas MUC16 mRNA levels did not vary (Fig. 1b), suggesting that Gal-3 positively controls the expression of MUC1 and MUC4 either at a transcriptional or post-transcriptional level
The samples could be separated into two subgroups that differed significantly in terms of expression levels: a first one characterized by low LGALS3 & low MUC4 and a second one with high LGALS3 & high MUC4 mRNA levels
Summary
Galectin-3 (Gal-3), which is a soluble β-galactoside-binding lectin encoded by LGALS3, shuttles from the nucleus to the cytosol, and is secreted in the extracellular milieu by a non-classical secretory pathway[1,2]. Allergen-challenged gal-3−/− mice exhibit reduced airway hyper-responsiveness and peri-bronchial fibrosis as well as decreased production of mucus compared with wild-type mice[12] These abnormalities may be related to the positive, but molecularly uncharacterized, effects of Gal-3 on type 1 collagen, α-smooth muscle actin and fibronectin, as well as on the production of interleukin (IL)-5, IL-12 and TGFβ.the molecular mechanisms underlying the effects panel: Sh1 cells were transfected with luciferase vector constructs containing wild-type or CARE-deleted MUC4 3′UTR, and co-transfected or not with pCMV6-XL4 gal-3 expression vector. Epithelial mucins are high molecular weight glycoproteins with numerous clustered O-glycan chains linked to tandem repeat domains of the peptide backbone They are classified as secreted (such as MUC2, MUC5AC or MUC5B) or membrane-associated mucins (such as MUC1, MUC4 or MUC16). Apart from studies focusing on miRNAs, very few studies have addressed the mechanisms responsible for the “hyper” stability of MUC transcripts
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