Persistent ER stress causes GPI anchor deficit to convert a GPI-anchored prion protein into pro-PrP via the ATF6-miR449c-5p-PIGV axis.

Endoplasmic reticulum (ER) stress and unfolded protein response are cells' survival strategies to thwart disruption of proteostasis. Tumor cells are continuously being challenged by ER stress. The prion protein, PrP, normally a glycosylphosphatidylinositol (GPI)-anchored protein exists as a pro-PrP retaining its GPI-peptide signal sequence in human pancreatic ductal cell adenocarcinoma (PDAC). Higher abundance of pro-PrP indicates poorer prognosis in PDAC patients. The reason why PDAC cells express pro-PrP is unknown. Here, we report that persistent ER stress causes conversion of GPI-anchored PrP to pro-PrP via a conserved ATF6-miRNA449c-5p-PIGV axis. Mouse neurons and AsPC-1, a PDAC cell line, express GPI-anchored PrP. However, continuous culture of these cells with the ER stress inducers thapsigargin or brefeldin A results in the conversion of a GPI-anchored PrP to pro-PrP. Such a conversion is reversible; removal of the inducers allows the cells to re-express a GPI-anchored PrP. Mechanistically, persistent ER stress increases the abundance of an active ATF6, which increases the level of miRNA449c-5p (miR449c-5p). By binding the mRNA of PIGV at its 3'-UTRs, miR449c-5p suppresses the level of PIGV, a mannosyltransferase pivotal in the synthesis of the GPI anchor. Reduction of PIGV leads to disruption of the GPI anchor assembly, causing pro-PrP accumulation and enhancing cancer cell migration and invasion. The importance of ATF6-miR449c-5p-PIGV axis is recapitulated in PDAC biopsies as the higher levels of ATF6 and miR449c-5p and lower levels of PIGV are markers of poorer outcome for patients with PDAC. Drugs targeting this axis may prevent PDAC progression.

Pro-prion, as a membrane adaptor protein for E3 ligase c-Cbl, facilitates the ubiquitination of IGF-1R, promoting melanoma metastasis.

Aberrant activation of receptor tyrosine kinase (RTK) is usually a result of mutation and plays important roles in tumorigenesis. How RTK without mutation affects tumorigenesis remains incompletely understood. Here we show that in human melanomas pro-prion (pro-PrP) is an adaptor protein for an E3 ligase c-Cbl, enabling it to polyubiquitinate activated insulin-like growth factor-1 receptor (IGF-1R), leading to enhanced melanoma metastasis. All human melanoma cell lines studied here express pro-PrP, retaining its glycosylphosphatidylinositol-peptide signal sequence (GPI-PSS). The sequence, PVILLISFLI in the GPI-PSS of pro-PrP, binds c-Cbl, docking c-Cbl to the inner cell membrane, forming a pro-PrP/c-Cbl/IGF-1R trimeric complex. Subsequently, IGF-1R polyubiquitination and degradation are augmented, which increases autophagy and tumor metastasis. Importantly, the synthetic peptide PVILLISFLI disrupts the pro-PrP/c-Cbl/IGF-1R complex, reducing cancer cell autophagy and mitigating tumor aggressiveness in vitro and in vivo. Targeting cancer-associated GPI-PSS may provide a therapeutic approach for treating human cancers expressing pro-PrP.

The complete mitochondrial genome of Agriotes fuscicollis Miwa, 1928 (Coleoptera: Elateridae).

In this study, we sequenced the complete mitochondrial genome of Agriotes fuscicollis Miwa, 1928 (Coleoptera: Elateridae). The results showed that the length of complete mitochondrial genome was 15,866 bp with 26.8% GC content, containing 39.6% A, 33.5% T, 16.8% C, 10% G. There were 13 protein-coding genes (PCGs), 22 transfer RNA genes, and 2 ribosomal RNA genes. Phylogenetic analysis showed that A. fuscicollis was closely related to Cryptalaus larvatus, Cryptalaus yamato, Pyrophorus divergens and Ignelater luminosus. The complete mitogenome of A. fuscicollis would contribute to the study of the phylogeny and evolution of Elateridae.

The complete mitochondrial genome of Pheropsophus occipitalis MacLeay, 1825 (Coleoptera: Carabidae).

Pheropsophus occipitalis MacLeay is a predatory enemy prey heavily on agricultural pests. The length of the complete mitochondrial genome of P. occipitalis was 16,800 bp with 20.4% GC content, including 41.2% A, 11.9% C, 8.4% G, 38.5% T. The genome encoded 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNA), two ribosomal RNA genes (rRNA). Phylogenetic analysis showed that P. occipitalis was clustered with Pheropsophus bimaculatus and Pheropsophus sobrinus. This study provided a scientific basis for the population genetics, phylogeny, and molecular taxonomy of P. occipitalis.

Melanoma migration is promoted by prion protein via Akt-hsp27 signaling axis.

Patients with metastatic melanoma have a poorer prognosis. Prion protein (PrP) in melanoma is known to play an important role in cancer cell migration and invasion by interacting with filamin A (FLNa), a cytolinker protein. To investigate if PrP may contribute to cancer cell mobility independent of its binding to FLNa, we knocked out PRNP in M2 melanoma cell, which lacked FLNa expression. We found that deletion of PRNP in M2 significantly reduced its motility. When PRNP was deleted, the level of Akt was decreased. As a consequence, phosphorylation of small heat shock protein (hsp27) was also reduced, which resulted in polymerization of F-actin rendering the cells less migratory. Accordingly, when PrP was re-expressed in PRNP null M2 cells, the mobility of the recurred cells was rescued, so were the expression levels of Akt and phosphorylated hsp27, resulting in a decrease in the polymerization of F-actin. These results revealed that PrP can play a FLNa independent role in cytoskeletal organization and tumor cell migration by modulating Akt-hsp27-F-actin axis.

NAV2 facilitates invasion of cutaneous melanoma cells by targeting SNAI2 through the GSK-3ß/ß-catenin pathway.

Previous studies have identified neuron navigator 2(NAV2) as an oncogene in several human tumors. However, the NAV2 gene expression changes and its role in the pathogenesis of cutaneous melanoma have not been clearly illustrated. Further investigations of NAV2 in cutaneous melanoma may provide new mechanistic insight and treatment strategy for this disease. Through immunohistochemistry assay and bioinformatics analysis, we found that melanoma tissues showed an upregulated expression of NAV2 which correlated with poor prognosis of cutaneous melanoma. To investigate the effect of NAV2 on the proliferation and invasion of melanoma, shNAV2 and NAV2-cDNA were transfected into melanoma cell lines. NAV2 overexpression significantly promoted melanoma cell proliferation, migration and invasion, while NAV2 silencing effectively inhibited this process. The potential underlying mechanisms were investigated using bioinformatics analysis, qRT-PCR, and western blot. Results showed that NAV2-mediated invasion of melanoma cells was driven by enhanced epithelial-mesenchymal transition, which was resulted from SNAI2 upregulation via the GSK-3ß/ß-catenin pathway. This study suggested that NAV2 could induce melanoma proliferation and invasion by epithelial-mesenchymal transition through the GSK-3ß/ß-catenin-SNAI2 pathway. Our findings on the pathological mechanisms of NAV2-associated cutaneous melanoma may contribute to the development of potential therapeutic strategy for melanoma.