Gasdermin-B Promotes Invasion and Metastasis in Breast Cancer Cells

Abstract

Gasdermin B (GSDMB) belongs to the Gasdermin protein family that comprises four members (GSDMA-D). Gasdermin B expression has been detected in some tumor types such as hepatocarcinomas, gastric and cervix cancers; and its over-expression has been related to tumor progression. At least four splicing isoforms of GSDMB have been identified, which may play differential roles in cancer. However, the implication of GSDMB in carcinogenesis and tumor progression is not well understood. Here, we uncover for the first time the functional implication of GSDMB in breast cancer. Our data shows that high levels of GSDMB expression is correlated with reduced survival and increased metastasis in breast cancer patients included in an expression dataset (>1,000 cases). We demonstrate that GSDMB is upregulated in breast carcinomas compared to normal breast tissue, being the isoform 2 (GSDMB-2) the most differentially expressed. In order to evaluate the functional role of GSDMB in breast cancer two GSDMB isoforms were studied (GSDMB-1 and GSDMB-2). The overexpression of both isoforms in the MCF7 breast carcinoma cell line promotes cell motility and invasion, while its silencing in HCC1954 breast carcinoma cells decreases the migratory and invasive phenotype. Importantly, we demonstrate that both isoforms have a differential role on the activation of Rac-1 and Cdc-42 Rho-GTPases. Moreover, our data support that GSMDB-2 induces a pro-tumorigenic and pro-metastatic behavior in mouse xenograft models as compared to GSDMB-1. Finally, we observed that although both GSDMB isoforms interact in vitro with the chaperone Hsp90, only the GSDMB-2 isoform relies on this chaperone for its stability. Taken together, our results provide for the first time evidences that GSDMB-2 induces invasion, tumor progression and metastasis in MCF7 cells and that GSDMB can be considered as a new potential prognostic marker in breast cancer.

Gene polymorphism linked to increased asthma and IBD risk alters gasdermin-B structure, a sulfatide and phosphoinositide binding protein

“…Subsequent association of the Gsdma3 N-terminal domain with the mitochondrial chaperone TRAP1 promotes the production of reactive oxygen species (ROS), causing mitochondrial stress and loss of membrane integrity. Interestingly, coimmunoprecipitation experiments identified the binding of GSDMB to HSP90β in breast cancer cells (8). The N-terminal domain of GSDMB did not induce autophagy (27),…”

“…The mouse genome contains three clusters of GSDM genes, encoding eight GSDMs (Gsdma1 to -3, Gsdmc1 to -4, and Gsdmd), but lacks the analog of the human GSDMB (also known as GSDML or PRO2521) (1). Based on the differential protein expressions in gastric and esophageal cancers, human GSDMA, GSDMC, and GSDMD are considered tumor suppressors whereas an overexpression of GSDMB in gastric, uterine cervix, and breast cancers was accompanied by tumor progression and metastasis (3)(4)(5)(6)(7)(8). The overexpression of GSDMC in metastatic melanoma cells is an exception to its apoptotic role (9).…”

Why is Chromosome 17q21 linked to Asthma?

“…A mouse or rat ortholog of the GSDMB gene has not been identified, and it may have evolved independently in humans through a GSDM gene duplication [18]. The human GSDMB gene consists of 12 exons and four different splice variants have been described, which differ in exons 6 and 7 of the GSDMB gene [19]. GSDMB has been linked to cancer progression and is expressed in human gastric, liver, colon and breast cancer cell lines and carcinomas [17,19].…”

“…The human GSDMB gene consists of 12 exons and four different splice variants have been described, which differ in exons 6 and 7 of the GSDMB gene [19]. GSDMB has been linked to cancer progression and is expressed in human gastric, liver, colon and breast cancer cell lines and carcinomas [17,19]. Although several genetic studies show a strong association of GSDMB with asthma, no functional studies to date have investigated the biological role of GSDMB in asthma and related airway cell types.…”

Genome-wide association studies in asthma: progress and pitfalls

“…58 The product of the ORMDL3 gene also at this locus has been the subject of greater study. ORMDL3 was found to be an inducible endoplasmic reticulum protein with characteristics of proteins involved in the unfolded protein response, which appears to regulate the expression of various proteins with connection to asthma pathology.…”