Synaptotagmin 12 (SYT12) Gene Expression Promotes Cell Proliferation and Progression of Lung Adenocarcinoma and Involves the Phosphoinositide 3-Kinase (PI3K)/AKT/Mammalian Target of Rapamycin (mTOR) Pathway

Abstract

Background: This study aimed to use bioinformatics analysis to compare data from tissue microarrays from patients with lung adenocarcinoma (LUAD) and normal lung tissue, and human lung adenocarcinoma cells with normal lung epithelial cells in vitro to investigate the role of synaptotagmin 12 (SYT12) gene expression in LUAD. Material/Methods: Human lung adenocarcinoma cell lines (A549, SPC-A-1, H1299, H1975, and PC9) and the normal HBE cell line were compared, and tumor xenografts were developed in mice. The Cancer Genome Atlas (TCGA) tissue microarray data were used to compare SYT12 expression and overall survival (OS). The in vivo and in vitro effects of down-regulation and upregulation of SYT12 were studied using short-interfering RNA (si-RNA) and overexpression plasmids, respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathway analysis, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and Western blot investigated the molecular mechanisms of SYT12 expression in LUAD. Results: SYT12 expression was increased in tissues from patients with LUAD from TCGA and was associated with advanced tumor stage and reduced prognosis. Knockdown of SYT12 suppressed the proliferation and migration of LUAD cells, and upregulation of SYT12 increased the proliferation and migration of LUAD cells in vitro. Phosphorylation of PIK3R3 activated the PI3K/AKT/mTOR pathway. In the mouse xenograft model, expression of SYT12 increased the volume and weight of the xenograft tumors. Conclusions: Bioinformatics analysis, human LUAD cells, and mouse xenograft studies showed that SYT12 acted as a possible oncogene by phosphorylation of PIK3R3 to activate the PI3K/AKT/mTOR signaling pathway.

The study of cancer cell in stromal environment through induced pluripotent stem cell–derived mesenchymal stem cells

“…5C). Vimentin 35,36 and SLUG 3 have been commonly used as EMT markers, as the previous study has shown to be correlated to tumor metastasis and cancer resistance toward drug treatment, while the clinical study has shown ICAM1, 37 FBP1, 38-40 SYT12, 41 and INHBE 42,43 to be related to poor prognosis, proliferation, invasiveness, and migratory properties of lung cancer; the MMP family of MMP13 and MMP14 has shown different trends with upregulation of MMP14 44,45 expression and downregulation of MMP13 46 expression while both have been identified to be related to the malignancy of lung cancer; SERPINE1 47,48 has been known to increase proliferation and tumor budding and inhibit apoptosis in primary tumors; S1003A 49 plays a role in regulating retinoic acid alpha that is found to promote tumor progression in several other cancers; TXNIP 50,51 plays a role in metabolic reprogramming and oxidative stress of cancer cells that can act as a tumor suppressor gene. Although our discovery shows a possibility of using iMSCs as a potential treatment for cancer, participation from other cells and functional systems is required for a better understanding.…”

SYT12 is a novel oncogene that promotes thyroid carcinoma progression and metastasis

“…To discover a gene that associates with PTC that could differentiate low-risk and high-risk PTC patients, we send 39 paired PTC samples for RNA sequencing and discovered that SYT12 was overexpressed in PTC tissues associated with nearby non-neoplastic thyroid tissues. There are a few reports about SYT12, and it has been found that played a crucial role in some cancers such as oral cancer and lung adenocarcinoma [10,11]. Jonklaas et al also showed that SYT12 could predict papillary thyroid cancer outcomes in a prospective cohort [12].…”

“…In recent years, variants of the human SYT12 were shown to be associated with some cancers [10,11]. Liu et al reported that SYT12 acted as a possible oncogene by activating the PI3K-AKT-mTOR signal channel in lung adenocarcinoma [11].…”

“…In recent years, variants of the human SYT12 were shown to be associated with some cancers [10,11]. Liu et al reported that SYT12 acted as a possible oncogene by activating the PI3K-AKT-mTOR signal channel in lung adenocarcinoma [11]. Keitaro et al also found that SYT12 played a crucial part in oral carcinoma and might be an innovative therapeutic target [10].…”

Potential roles of synaptotagmin family members in cancers: Recent advances and prospects

“…SYT12 also promoted LUAD cell proliferation and migration in vitro and increased the weight and volume of tumors in mice xenograft models. In parallel, SYT12 could activate the PI3K/AKT/mTOR 10.3389/fmed.2022.968081 signaling pathway by increasing the level of phosphorylation of PIK3R3 (39).…”