Reduced emerin expression marks gastric cancer progression and invasive nuclear remodeling

Abstract

Altered nuclear morphology is a defining diagnostic feature of malignancy, and nuclear structure is increasingly recognized as a functional regulator of cancer cell invasion. The inner nuclear membrane protein emerin maintains nuclear architecture and restrains invasive phenotypes in breast cancer models, but whether emerin expression is similarly altered in gastric cancer has not been established. Here, we analyzed emerin protein expression, nuclear morphology, and impeded migration in nonmalignant and malignant gastric cell lines. In parallel, emerin protein expression and nuclear envelope localization across gastric cancer was determined using patient tissue microarrays. Emerin was abundant at the nuclear envelope in cancer-adjacent and noncancerous gastric epithelium but was reduced across multiple gastric cancer histologies, including adenocarcinoma, signet-ring cell carcinoma, mucinous adenocarcinoma, neuroendocrine carcinoma, squamous cell carcinoma, and metastatic lesions. Reduced emerin at the nuclear envelope was most strongly associated with higher-grade tumors, with grade 2 and grade 3 cancers exhibiting significantly lower nuclear envelope scores than noncancerous tissue and grade 1 tumors. Consistent with the patient tissue data, the gastric cancer cell lines AGS and MKN1 expressed less emerin protein than noncancerous gastric epithelial control cells HFE-145. Consistent with studies in breast cancer cells, gastric cells with reduced emerin expression also had smaller nuclei and increased impeded migration through 8 micron pores. These findings support a model in which reduced nuclear envelope emerin is a conserved feature of invasive epithelial tumor progression and a candidate biomarker of gastric cancer nuclear remodeling.