miR-193a Directly Targets PSEN1 and Inhibits Gastric Cancer Cell Growth, the Activation of PI3K/Akt Signaling Pathway, and the Epithelial-to-Mesenchymal Transition

Abstract

Background. Gastric cancer, a kind of gastrointestinal malignancy, is the second type of leading death cancer. miR-193a is a key tumor suppressor in several diseases. PSEN1 is mainly related to Alzheimer’s disease and may be involved in the cleavage of the Notch receptor. Material and Methods. RT-PCR and western blot were applied to evaluate miR-193a and the expression level of PSEN1. Luciferase reporter assay was applied to verify whether PSEN1 was a target of miR-193a. The Kaplan–Meier method was employed to calculate the 5-year overall survival of gastric cancer patients. Results. miR-193a was downregulated in gastric cancer tissues and cell lines, and downregulation of miR-193a predicted poor 5-year overall survival of gastric cancer. miR-193a inhibited the proliferation and the activation of the PI3K/AKT signaling pathway in gastric cancer cells. miR-193a inhibited gastric cancer tumor growth in vivo. miR-193a impaired cell invasion and epithelial-to-mesenchymal transition (EMT) in HGC-27 cells. In addition, PSEN1 was a direct target of miR-193a and PSEN1 reversed partial functions of miR-193a in cell proliferation and invasion. Conclusion. miR-193a prominently decreased the proliferation, invasion, and activation of the PI3K/Akt signaling pathway and the abilities of epithelial-to-mesenchymal transition in gastric cancer cells. The newly identified miR-193a/PSEN1 axis provides novel insight into the pathogenesis of gastric cancer.

MiR-654-3p Constrains Proliferation, Invasion, and Migration of Sinonasal Squamous Cell Carcinoma via CREB1/PSEN1 Regulatory Axis

“…PSEN1, mainly located in the endoplasmic reticulum, is a ubiquitously expressed protein with multiple transmembrane domains ( Li et al, 2016 ). Earlier studies denoted that miR-193a downregulates the PSEN1 level to constrain cell proliferation and invasion of gastric cancer ( Pan et al, 2021 ), which was in accord with our results. We confirmed through cellular experiments and rescue experiments that miR-654-3p modulated CREB1/PSEN1 axis to constrain proliferation, migration, and invasion and induce apoptosis of SNSCC cells.…”

“…Besides, PSEN1/γ-secretase complex is conducive to the processing of P-cadherin, N-cadherin, and E-cadherin, thus modulating cell movement and invasion (Li et al, 2016). The result that PSEN1 fosters cancer cell EMT was also confirmed in gastric cancer and lung adenocarcinoma (Guo et al, 2020;Pan et al, 2021). Hence, we speculated that PSEN1 could modulate SNSCC cell EMT and verified the promotion effect by assessing expression of EMT-related proteins in multiple cotransfection groups, whereas miR-654-3p could modulate PSEN1 to hamper SNSCC cell EMT, which was in accord with earlier studies.…”

Computational Pipeline to Identify Gene signatures that Define Cancer Subtypes

“…These 3 genes also have inhibitors available, such as ladademstat, which can potentially target KDM1A (LSD1) (Salamero, et al, 2020), thus can be used to inhibit the growth of astrocytoma glioma. Similarly, miR-193a can target PSEN1 (Pan, et al, 2021), which can potentially be used to inhibit the growth of oligodendrogliomas. Further, inhibitors for MMP3 are still being tested in cancer (Winer, et al, 2018).…”

“…Further, we discovered two targetable genes with current on the market drugs. PSEN1 can be targeted using miR-193a for oligodendrogliomas (Pan et al, 2021). Similarly, KDM1A (LSD1) can be targeted with ladademstat to potentially treat astrocytoma (Lu, et al, 2018;Wang, et al, 2022).…”

PSEN1 is associated with colon cancer development via potential influences on PD-L1 nuclear translocation and tumor-immune interactions

“…However potential actions of the individual γ-secretase components, especially the proteolytically active presenilin 1 (PSEN1) subunit and the potential links between PSEN1 and caners have yet to be fully addressed. Recently, miR-193a, miR-654-3p and other selective PSEN1 inhibitions have been reported to hamper gastric ( 12 ), SNSCC ( 13 ) and Leukemias ( 14 ) cancer hallmarks, respectively. Thus, we explored PSEN1’s functional panorama, an interesting connection between PSEN1 and PD-L1 attracted our attention.…”