Lnc-PFAR facilitates autophagy and exacerbates pancreatic fibrosis by reducing pre-miR-141 maturation in chronic pancreatitis

Abstract

Chronic pancreatitis (CP) is described as progressive inflammatory fibrosis of pancreas, accompanied with irreversible impaired endocrine and exocrine insufficiency. Pancreatic stellate cells (PSCs) are widely distributed in the stroma of the pancreas and PSCs activation has been shown as one of the leading causes for pancreatic fibrosis. Our previous study has revealed that autophagy is dramatically activated in CP tissues, which facilitates PSCs activation and pancreatic fibrosis. Long non-coding RNAs (LncRNAs) have been recognized as crucial regulators for fibrosis-related diseases. LncRNAs interact with RNA binding protein or construct competitive endogenous RNA (ceRNA) hypothesis which elicited the fibrotic processes. Until now, the effects of lncRNAs on PSCs activation and pancreatic fibrosis have not been clearly explored. In this study, a novel lncRNA named Lnc-PFAR was found highly expressed in mouse and human CP tissues. Our data revealed that Lnc-PFAR facilitates PSCs activation and pancreatic fibrosis via RB1CC1-induced autophagy. Lnc-PFAR reduces miR-141 expression by suppressing pre-miR-141 maturation, which eventually upregulates the RB1CC1 and fibrosis-related indicators expression. Meanwhile, Lnc-PFAR enhanced PSCs activation and pancreatic fibrosis through trigging autophagy. Our study interrogates a novel lncRNA-induced mechanism in promoting the development of pancreatic fibrosis, and Lnc-PFAR is suggested to be a prospective therapeutic target in clinical scenarios.

Current Trends and Research Hotspots in Pancreatic Stellate Cells: A Bibliometric Study

“…Chronic hyperglycemia can activate PSCs and promote the interaction between PSCs and pancreatic cancer cells ( 10 ). Activated PSCs play a crucial role in the development of pathological pancreatic fibrosis ( 11 , 12 ), which characterizes chronic pancreatitis ( 13 , 14 ) and pancreatic cancer-associated desmoplastic reaction ( 7 , 15 ). Therefore, chronic pancreatitis and pancreatic cancer can be treated using anti-fibrotic agents, such as vitamin analogs, targeting PSCs ( 16 ).…”

The Role of MicroRNAs in Pancreatitis Development and Progression

“…TGFβ signaling plays an essential role in activating PSCs during CP via induction of expression of several matrix metalloproteinases and tissue inhibitors of metalloproteinases, resulting in extracellular matrix remodeling, deposition of collagen fibers, and increased stiffness of the tissues. Zhang et al demonstrated that TGFβ increases lnc-PFAR levels, which then binds to premature miR-141-5p, blocks its maturation, and activates fibrosis and autophagy in PSCs [ 119 ] ( Figure 6 ). Furthermore, miR-141-5p prevents autophagy by binding to 3′UTR of Retinoblastoma coiled-coil protein 1, inhibiting ULK1 dephosphorylation and reducing autophagy.…”

“…However, in CP, the levels of miR-141-5p are downregulated, and thus, the fibrosis and autophagy of PSCs are increased. Importantly, in vivo studies showed that delivery of lnc-PFAR enhanced fibrosis in CP, as shown by H&E and Masson’s Trichrome stains, on molecular markers of fibrosis such as fibronectin, collagen I/III, and α-SMA [ 119 ].…”

Vitamin D: A Potential Star for Treating Chronic Pancreatitis

“…Autophagy is a cellular process in degrading of long-lived proteins and organelles and misfolded proteins in the cytosol for maintaining cellular homeostasis, which has been linked to many states of human health and disease ( Xu et al, 2018 ; Zhang et al, 2021 ). Recently, VD has been demonstrated to alleviate ethanol-induced hepatotoxicity by enhancing autophagy ( Yuan et al, 2021 ).…”

“…Additionally, inhibiting autophagy can also suppress pancreatic fibrosis through promoting ECM degradation by decreasing the expression of TGF-β1 and increasing MMPs/TIMPs ratio ( Li et al, 2018a ). Retinoblastoma coiled coil protein 1-induced autophagy can facilitate PSC activation and pancreatic fibrosis in CP ( Li et al, 2018c ; Zhang et al, 2021 ). Contrarily, PDGF inhibits autophagy in HSC and increases the release of extracellular vesicle (EV) ( Gao et al, 2020 ), while the release of EV can promote the interaction between cells and fibrosis ( Xu et al, 2018 ), suggesting that autophagy in HSC alleviated liver fibrosis by reducing the release of HSC-derived EV ( Gao et al, 2020 ).…”