Stomatin-like Protein 2 Is Overexpressed in Cancer and Involved in Regulating Cell Growth and Cell Adhesion in Human Esophageal Squamous Cell Carcinoma

Abstract

Purpose: Stomatin-like protein 2 (SLP-2) is a novel and unusual stomatin homologue of unknown functions. It has been implicated in interaction with erythrocyte cytoskeleton and presumably other integral membrane proteins, but not directly with the membrane bilayer.We show here the involvement of SLP-2 inhuman esophageal squamous cell carcinoma (ESCC), lung cancer, laryngeal cancer, and endometrial adenocarcinoma and the effects of SLP-2 on ESCC cells. Experimental Design: Previous work of cDNA microarray in our laboratory revealed that SLP-2 was significantly up-regulated in ESCC. The expression of SLP-2 was further evaluated in human ESCC, lung cancer, laryngeal cancer, and endometrial adenocarcinoma by semiquantitative reverse transcription-PCR, Western blot, and immunohistochemistry. Mutation detection of SLP-2 exons was done by PCR and automated sequencing. Antisense SLP-2 eukaryotic expression plasmids were constructed and transfected into human ESCC cell line KYSE450. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, clonogenecity assay, flow cytometry assay, nude mice tumorigenetic assay, and cell attachment assay were done to investigate the roles of SLP-2 gene. Results: All tumor types we tested showed overexpression of SLP-2 compared with their normal counterparts (P V 0.05). Moreover, immunohistochemistry analysis of mild dysplasia, severe dysplasia, and ESCC showed that overexpression of SLP-2 occurred in premalignant lesions. Mutation analysis indicated that no mutation was found in SLP-2 exons. KYSE450 cells transfected with antisense SLP-2 showed decreased cell growth, proliferation, tumorigenecity, and cell adhesion. Conclusions: SLP-2 was first identified as a novel cancer-related gene overexpressed in human ESCC, lung cancer, laryngeal cancer, and endometrial adenocarcinoma. Decreased cell growth, cell adhesion, and tumorigenesis in the antisense transfectants revealed that SLP-2 may be important in tumorigenesis.

SLP-2 negatively modulates mitochondrial sodium–calcium exchange

“…Phylogenic analysis revealed that SLP-2 was acquired through the mitochondrial endosymbiosis and belongs to a different lineage than other stomatin-like proteins [21]. SLP-2 is highly expressed in several types of human tumors [22], and high SLP-2 levels are associated with decreased survival of patients suffering from primary invasive breast cancer [23], suggesting a role for SLP-2 in tumorigenesis.…”

MicroRNA-10b Promotes Migration and Invasion through KLF4 in Human Esophageal Cancer Cell Lines

“…Western Blot-Western blots were performed as previously described (37). Protein bands were detected by chemiluminescence using the ECL system (Vigorous Biotech, Beijing, China) according to the manufacture's protocol.…”

Increased levels of SLP-2 correlate with poor prognosis in gastric cancer

“…Moreover, a luciferase reporter assay indicated that SLP-2 regulates MMP-9 expression in an NF-jB-dependent manner, suggesting that SLP-2 may be a component of the NF-jB signaling pathway [14]. Consistent with this possibility, fibronectin 1, a downstream target of NF-jB, is downregulated following SLP-2 knockdown in ESCC cells, and fibronectin 1 and SLP-2 expression levels are significantly correlated in ESCC tissues [9]. Future studies to determine the cellular mechanisms by which SLP-2 promotes GC progression are warranted.…”

“…It has been suggested that stomatins are involved in the organization of the peripheral cytoskeleton, the formation of sphingolipid-and cholesterolrich lipid rafts, and the assembly of ion channels and mechanosensation receptors [19,20]. SLP-2 expression is upregulated in multiple tumor types, including ESCC, endometrial adenocarcinoma, LSCC, breast cancer, PSCC, and glioma [4,[9][10][11][12][13][14], but the mechanisms leading to SLP-2 overexpression in human tumors are not well known. SLP-2 has been shown to enhance invasiveness in glioma cells, potentially through the upregulation of MMP-9.…”

“…Recently, SLP-2 has been shown to be upregulated and involved in progression and development in several types of cancer, including esophageal squamous cell carcinoma (ESCC), endometrial adenocarcinoma, laryngeal squamous cell carcinoma (LSCC), pulmonary squamous cell carcinoma (PSCC), breast cancer, and glioma [4,[8][9][10][11][12][13][14]. In ESCC, SLP-2 is one of the most differentially expressed cancerrelated genes compared with paired adjacent normal tissues, and knockdown of SLP-2 reduces the growth rate of ESCC cells in vitro and in vivo and inhibits cell attachment [8,9]. SLP-2 is also associated with cancer cell survival, because silencing SLP-2 enhances the sensitivity of cancer cells to chemotherapeutics [4].…”