MIEN1

The exhaustion of T-cells is a primary factor contributing to immune dysfunction in cancer. Long non-coding RNAs (lncRNAs) play a significant role in the advancement, survival, and treatment of Uterine Corpus Endometrial Carcinoma (UCEC). Nevertheless, there has been no investigation into the involvement of lncRNAs associated with T-cell exhaustion (TEXLs) in UCEC. The goal of this work is to establish predictive models for TEXLs in UCEC and study their related immune features.

Using transcriptome and single-cell sequencing data from The Cancer Genome Atlas and Gene Expression Omnibus databases, we employed co-expression analysis and univariate Cox regression to identify prognostic-associated TEXLs (pTEXLs). The prognostic model was developed using the Least Absolute Contraction and Selection Operator. The immunotherapy characteristics of the prognostic model risk score were studied. Then molecular subgroups were identified through non-negative Matrix Factorization based on pTEXLs. The identification of co-expressed genes was done using a weighted correlation network analysis. Subsequently, a diagnostic model for UCEC was created. In-depth investigations, both in vitro and in vivo, were carried out to elucidate the molecular mechanism of the key gene within the diagnostic model.

Receiver operating characteristic curve, calibration curve, and decision curve analysis proved the validity of the predictive models established according to pTEXLs. The subgroup with lower risk scores in the prognostic model has better responses to blocking immune checkpoint therapy. Single-cell analysis suggests that the expression level of MIEN1 is relatively high in immune cells among diagnostic genes. Furthermore, the targeted suppression of MIEN1 via sh-MIEN1 diminishes the proliferative, migratory, and invasive capacities of UCEC cells, potentially associated with CD8⁺ T cell exhaustion.

The association between TEXLs and UCEC was methodically elucidated by our investigation. A stable pTEXLs risk prediction model and a diagnosis model for UCEC were also established.

Migration and invasion enhancer 1 (MIEN1) overexpression characterizes several cancers and facilitates cancer cell migration and invasion. Leveraging conserved ITAM and prenylation motifs within MIEN1, we identified potent anti-cancer peptides. Among them, bioactive peptides LA3IK and RP-7 induced pronounced transcriptomic and protein expression changes at sub-IC50 concentrations. The peptides effectively inhibited genes and proteins driving cancer cell migration, invasion, and EMT pathways, concurrently suppressing EGF-induced NF-κB nuclear translocation in metastatic breast cancer cells. Specifically, peptides targeted the same signal transduction pathway initiated by MIEN1. Molecular docking and circular dichroism spectroscopy indicated the formation of MIEN1-peptide complexes. The third-positioned isoleucine in LA3IK and CVIL motif in RP-7 were crucial for inhibiting breast cancer cell migration. This is evident from the limited migration inhibition observed when MDA-MB-231 cells were treated with scrambled peptides LA3IK SCR and RP-7 SCR. Additionally, LA3IK and RP-7 effectively suppressed tumor growth in an orthotopic breast cancer model. Notably, mice tolerated high peptide doses of up to 90 mg/Kg well, surpassing significantly lower doses of 5 mg/Kg intravenously (iv) and 30 mg/Kg intraperitoneally (ip) used in both in vivo pharmacokinetic studies and orthotopic mouse model assays. D-isomers of LA3IK and RP-7 showed enhanced anti-cancer activity compared to their L-isomers. D-LA3IK remained stable in mouse plasma for 24 h with 75% remaining, exhibiting superior pharmacokinetic properties over D/L-RP-7. In summary, our findings mark the first report of short peptides based on MIEN1 protein sequence capable of inhibiting cancer signaling pathways, effectively impeding cancer progression both in vitro and in vivo.

It is well-recognized that blood flow at branches and bends of arteries generates disturbed shear stress, which plays a crucial in driving atherosclerosis. Flow-generated fluid shear stress (FSS), as one of the key hemodynamic factors, is appreciated for its critical involvement in regulating angiogenesis to facilitate wound healing and tissue repair. Endothelial cells can directly sense FSS but the mechanobiological mechanism by which they decode different patterns of FSS to trigger angiogenesis remains unclear. In the current study, laminar shear stress (LSS, 15 dyn/cm² ) was employed to mimic physiological blood flow, while disturbed shear stress (DSS, ranging from 0.5 ± 4 dyn/cm² ) was applied to simulate pathological conditions. The aim was to investigate how these distinct types of blood flow regulated endothelial angiogenesis. Initially, we observed that DSS impaired angiogenesis and downregulated endogenous vascular endothelial growth factor B (VEGFB) expression compared to LSS. We further found that the changes in membrane protein, migration and invasion enhancer 1 (MIEN1) play a role in regulating ERK/MAPK signaling, thereby contributing to endothelial angiogenesis in response to FSS. We also showed the involvement of MIEN1-directed cytoskeleton organization. These findings suggest the significance of shear stress in endothelial angiogenesis, thereby enhancing our understanding of the alterations in angiogenesis that occur during the transition from physiological to pathological blood flow.