Downregulation of endometrial mesenchymal marker SUSD2 causes cell senescence and cell death in endometrial carcinoma cells

Abstract

The cause of death among the majority of endometrial cancer patients involves migration of cancer cells within the peritoneal cavity and subsequent implantation of cancer spheroids into neighbouring organs. It is, thereby, important to identify factors that mediate metastasis. Cell adhesion and migration are modified by the mesenchymal stem cell (MSC) marker Sushi domain containing 2 (SUSD2), a type I transmembrane protein that participates in the orchestration of cell adhesion and migration through interaction with its partner Galactosidase-binding soluble-1 (LGALS1). MSCs have emerged as attractive targets in cancer therapy. Human endometrial adenocarcinoma (Ishikawa) cells were treated with TGFβ (10 ng/ml) for 72h. SUSD2, LGALS1 and MKI67 transcript levels were quantified using qRT-PCR. The proportion of SUSD2 positive (SUSD2+) cells and SMAD2/3 abundance were quantified by FACS and Western blotting, respectively. Senescent cells were identified with β-galactosidase staining; cell cycle and cell death were quantified using Propidium Iodide staining. Treatment of endometrial cancer cells (Ishikawa cells) with TGFβ (10 ng/ml) significantly decreased SUSD2 transcript levels and the proportion of SUSD2 positive cells. Silencing of SUSD2 using siRNA resulted in senescence and cell death of Ishikawa cells via activation of SMAD2/3. These findings suggest that SUSD2 counteracts senescence and cell death and is thus a potential chemotherapeutic target in human endometrial cancer.

Impact of Sustained Transforming Growth Factor-β Receptor Inhibition on Chromatin Accessibility and Gene Expression in Cultured Human Endometrial MSC

“…For example, opening of chromatin at and upstream of the SUSD2 promoter corresponded to increased abundance of SUSD2 + eMSC in A83-01 cultures. Interestingly, SUSD2 has been shown to prevent senescence and cell death in tumor cells ( Zhang et al, 2017 ), suggesting its induction is important for expansion of cultured eMSC.…”

Expression of sushi domain containing two reflects the malignant potential of gastric cancer

“…The present study presents the first evidence, to our knowledge, that SUSD2 acts as an oncogene in GC. 20 We show here that inhibiting SUSD2 mRNA expression using a specific siRNA inhibits cell proliferation, invasion, and migration, indicating that SUSD2 is required to establish the malignant phenotype of GC cells. To address this issue in more detail, we performed PCR array analysis and found that FZD7, CDH2, TGFB1, SPARC, ITGA5, and ZWB1 mRNAs were overexpressed in concert with SUSD2.…”

“…SUSD2 is expressed in endometrial carcinoma cells, and suppressing its expression following treatment with TGFβ or a specific siRNA increases apoptosis and senescence. The present study presents the first evidence, to our knowledge, that SUSD2 acts as an oncogene in GC …”

Proteomic analysis identifies highly expressed plasma membrane proteins for detection and therapeutic targeting of specific breast cancer subtypes

“…Elevated expression of SUSD2 is associated with increased tumor invasion and decreased survival in a mouse model [ 36 ]. Silencing of SUSD2 expression in endometrial carcinoma cells results in cell death [ 37 ]. Thus, it has been suggested that reducing expression of this protein might be a therapeutically useful strategy.…”