The epithelial cell adhesion molecule (EpCAM) is a single transmembrane protein on the cell surface. Given its strong expression on epithelial cells and epithelial cell-derived tumors, EpCAM has been identified as a biomarker for circulating tumor cells (CTCs) and exosomes and a target for cancer therapy. As a cell adhesion molecule, EpCAM has a crystal structure that indicates that it forms a cis-dimer first and then probably a trans-tetramer to mediate intercellular adhesion. Through regulated intramembrane proteolysis (RIP), EpCAM and its proteolytic fragments are also able to regulate multiple signaling pathways, Wnt signaling in particular. Although great progress has been made, increasingly more findings have revealed the context-specific expression and function patterns of EpCAM and their regulation processes, which necessitates further studies to determine the structure, function, and expression of EpCAM under both physiological and pathological conditions, broadening its application in basic and translational cancer research.

Although great progress has been achieved in cancer treatment in the past decades, lung cancer remains the leading cause of cancer death, which is partially caused by the fact that most lung cancers are diagnosed at advanced stages. To improve the sensitivity and specificity of lung cancer diagnosis, the underlying mechanisms of current diagnosis methods are in urgent need to be explored. Herein, we find that the expression of EpCAM, the widely used molecular marker for tumor cell characterization and isolation, is strongly upregulated in primary lung tumors, which is caused by both gene amplification and promoter hypomethylation. In contrast, EpCAM expression is severely repressed in metastatic lung tumors, which can be reversed by epigenetic drugs, DNMT inhibitor 5-aza-dC and HDAC inhibitor MS-275. Moreover, tumor-associated macrophages (TAMs) impede EpCAM expression probably through TGFβ-induced EMT signaling. These findings unveil the dynamic expression patterns of EpCAM and differential roles of epigenetic modification in EpCAM expression in primary and metastatic lung tumors, providing novel insights into tumor cell isolation and lung cancer diagnosis.

Different from the well-studied canonical NF-κB member RelA, the role of the noncanonical NF-κB member NF-κB2 in solid tumors, and lung cancer in particular, is poorly understood. Here we report that in contrast to the tumor-promoting role of RelA, NF-κB2 intrinsic to lung epithelial and tumor cells had no marked effect on lung tumorigenesis and progression. On the other hand, NF-κB2 limited dendritic cell number and activation in the lung but protected lung macrophages and drove them to promote lung cancer through controlling activation of noncanonical and canonical NF-κB, respectively. NF-κB2 was also required for B cell maintenance and T cell activation. The antitumor activity of lymphocyte NF-κB2 was dominated by the protumor function of myeloid NF-κB2; thus, NF-κB2 has an overall tumor-promoting activity. These studies reveal a cell type–dependent role for NF-κB2 in lung cancer and help understand the complexity of NF-κB action and lung cancer pathogenesis for better design of NF-κB–targeted therapy against this deadliest cancer.

Currently commercialized CAR-T cell therapies targeting CD19 and BCMA show great efficacy to cure B cell malignancies. However, intravenous infusion of these CAR-T cells severely destroys both transformed and normal B cells in most tissues and organs, in particular lung, leading to a critical question that what the impact of normal B cell depletion on pulmonary diseases and lung cancer is. Herein, we find that B cell frequency is remarkably reduced in both smoking carcinogen-treated lung tissues and lung tumors, which is associated with advanced cancer progression and worse patient survival. B cell depletion by anti-CD20 antibody significantly accelerates the initiation and progression of lung tumors, which is mediated by repressed tumor infiltration of T cells and macrophage elimination of tumor cells. These findings unveil the overall antitumor activity of B cells in lung cancer, providing novel insights into both mechanisms underlying lung cancer pathogenesis and clinical prevention post CAR-T cell therapy.

Gastric cancer (GC) has become the first malignant tumor with highest incidence rate and mortality of cancer in China, finding therapeutic targets for gastric cancer is of great significant for improving the survival rate of patients with GC. Recently, many of studies have shown that LncRNAs is involved in multiple biological progresses in the development of GC. This study, we screened for abnormally high expression of LncSHANK3 in GC through the TCGA database, and found that LncSHANK3 sponge adsorbs miR-4530, further competing with MNX1 and binding to miR-4530. We demonstrated the interaction between LncSHANK3 and miR-4530 through luciferase reporting analysis, with miR-4530 negatively regulating MNX1.Through CCK8, colony formation, transwell, and wound healing assays, it was found that LncSHANK3 affects the occurrence of GC through cell proliferation, migration and invasion. In conclusion, LncSHANK3/miR-4530/MNX1 axis is a potential mechanism for the treatment of GC.