COMP promotes pancreatic fibrosis by activating pancreatic stellate cells through CD36-ERK/AKT signaling pathways.

Pancreatic fibrosis is one of the most important pathological features of chronic pancreatitis (CP) and pancreatic stellate cells (PSCs) are the key cells of fibrosis. As an extracellular matrix (ECM) glycoprotein, cartilage oligomeric matrix protein (COMP) is critical for collagen assembly and ECM stability and recent studies showed that COMP exert promoting fibrosis effect in the skin, lungs and liver. However, the role of COMP in activation of PSCs and pancreatic fibrosis remain unclear. We aimed to investigate the role and specific mechanisms of COMP in regulating the profibrotic phenotype of PSCs and pancreatic fibrosis. ELISA method was used to determine serum COMP in patients with CP. Mice model of CP was established by repeated intraperitoneal injection of cerulein and pancreatic fibrosis was evaluated by Hematoxylin-Eosin staining (H&E) and Sirius red staining. Immunohistochemical staining was used to detect the expression changes of COMP and fibrosis marker such as α-SMA and Fibronectin in pancreatic tissue of mice. Cell Counting Kit-8, Wound Healing and Transwell assessed the proliferation and migration of human pancreatic stellate cells (HPSCs). Western blotting, qRT-PCR and immunofluorescence staining were performed to detect the expression of fibrosis marker, AKT and MAPK family proteins in HPSCs. RNA-seq omics analysis as well as small interfering RNA of COMP, recombinant human COMP (rCOMP), MEK inhibitors and PI3K inhibitors were used to study the effect and mechanism of COMP on activation of HPSCs. ELISA showed that the expression of COMP significantly increased in the serum of CP patients. H&E and Sirius red staining analysis showed that there was a large amount of collagen deposition in the mice in the CP model group and high expression of COMP, α-SMA, Fibronectin and Vimentin were observed in fibrotic tissues. TGF-β1 stimulates the activation of HPSCs and increases the expression of COMP. Knockdown of COMP inhibited proliferation and migration of HPSCs. Further, RNA-seq omics analysis and validation experiments in vitro showed that rCOMP could significantly promote the proliferation and activation of HPSCs, which may be due to promoting the phosphorylation of ERK and AKT through membrane protein receptor CD36. rCOMP simultaneously increased the expression of α-SMA, Fibronectin and Collagen I in HPSCs. In conclusion, this study showed that COMP was up-regulated in CP fibrotic tissues and COMP induced the activation, proliferation and migration of PSCs through the CD36-ERK/AKT signaling pathway. COMP may be a potential therapeutic candidate for the treatment of CP. Interfering with the expression of COMP or the communication between COMP and CD36 on PSCs may be the next direction for therapeutic research.

Wang Y ，Li HT ，Liu G ，Jiang CS ，Ni YH ，Zeng JH ，Lin X ，Wang QY ，Li DZ ，Wang W ，Zeng XP ... -  《-》

HSCs-derived COMP drives hepatocellular carcinoma progression by activating MEK/ERK and PI3K/AKT signaling pathways.

Li Q ，Wang C ，Wang Y ，Sun L ，Liu Z ，Wang L ，Song T ，Yao Y ，Liu Q ，Tu K ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》

P-element-Induced Wimpy-Testis-Like Protein 1 Regulates the Activation of Pancreatic Stellate Cells Through the PI3K/AKT/mTOR Signaling Pathway.

Pancreatic fibrosis is the main pathological characteristic of chronic pancreatitis (CP) and pancreatic cancer. Pancreatic stellate cells (PSCs) play a critical role in pancreatic fibrosis. Any targets that may have an impact on the activation of PSCs could become potential treatment candidates for CP and pancreatic cancer. Our goal was to investigate the effect of P-element-induced wimpy-testis (PIWI) protein 1 (PIWIL1) on PSC activation. Lentivirus-based RNA interference (RNAi) and overexpression vector construction were used to knock down and over-express the PIWIL1 protein. Immunocytofluorescent staining, western blotting, wound healing assay, transwell assay, and phalloidin staining were used to investigate the effects of PIWIL1 on the secretion of extracellular matrix components (EMC), actin cytoskeleton, and on the invasion and migration abilities of primary PSCs isolated from C57BL/6 mice. Moreover, pancreatic fibrosis was induced by L-arginine in C57BL/6 mice. The expression of PIWIL1 and collagen deposition in vivo were tested by western blotting and Sirius red staining. Expression levels of collagen I, collagen III, and α-smooth muscle actin were significantly decreased in the LV-PIWIL1 group. Compared with the si-PIWIL1 group, significant differences were observed in the expression of desmin, p-PI3K, p-AKT, and p-mTOR in the LV-PIWIL1 group. Furthermore, PIWIL1 suppressed the PSCs' invasion and migration abilities. In a rescue experiment, the PI3K/AKT/mTOR signaling pathway was found to be the underlying mechanism in PSCs activation mediated by PIWIL1. Our findings suggest that PIWIL1 inhibits the activation of PSCs via the PI3K/AKT/mTOR signaling pathway. PIWIL1 is a potential therapeutic target for pancreatic fibrosis.

Xue R ，Zhou J ，Wu J ，Meng Q ，Gong J ，Shen L ... -  《-》

Galectin-1 expression in activated pancreatic satellite cells promotes fibrosis in chronic pancreatitis/pancreatic cancer via the TGF-β1/Smad pathway.

Tang D ，Wu Q ，Zhang J ，Zhang H ，Yuan Z ，Xu J ，Chong Y ，Huang Y ，Xiong Q ，Wang S ，Tian Y ，Lu Y ，Ge X ，Shen W ，Wang D ... -  《-》

Tcf21 Alleviates Pancreatic Fibrosis by Regulating the Epithelial-Mesenchymal Transformation of Pancreatic Stellate Cells.

The activation of pancreatic stellate cells (PSCs) plays a key role in the occurrence and development of chronic pancreatitis (CP) and pancreatic fibrosis, which is related to the process of epithelial-mesenchymal transition (EMT). This study was designed to investigate the effect and mechanism of Tcf21 (one of tumor suppressor genes) on pancreatic inflammation and fibrosis in vivo and in vitro. C57BL/6 male mice were intraperitoneally injected with caerulein for 6 weeks to establish CP animal model. Fixed pancreatic tissue paraffin-embedded sections were used for immunohistochemistry staining of Tcf21, fibrosis-related markers (α-SMA), interstitial markers (Vimentin) and epithelial markers (E-cadherin). Western blotting and qRT-PCR assay were performed to analyze the change of expression of the above markers after stimulation of TGF-β1 or overexpressed Tcf21 lentivirus transfection in human pancreatic stellate cells (HPSCs). The pancreatic expression of α-SMA and Vimentin of CP mice significantly increased, while the expression of Tcf21 and E-cadherin significantly decreased. TGF-β1 could promote activation and EMT process of HPSCs, and inhibited the expression of Tcf21. Overexpression of Tcf21 could significantly down-regulate the expression of α-SMA, Fibronectin and Vimentin, and up-regulated the expression of ZO-1 of HPSCs. Cell Counting Kit-8 assay and scratch wound-healing assay results showed that overexpression of Tcf21 could significantly inhibit the cell migration and proliferation of HPSCs. Overexpression of Tcf21 could significantly alleviate the activation, proliferation, migration of PSCs by regulating the EMT process. Tcf21 had a potential prospect of a new target for CP therapy.

Ni YH ，Wang R ，Wang W ，Li DZ ，Liu G ，Jiang CS ，Wang Y ，Lin X ，Zeng XP ... -  《-》