Highlights of This Issue

Abstract

Gastric cancer remains a leading cause of cancer mortality worldwide. Dopamine and cAMP-regulated phosphoprotein, Mr 32000 (DARPP-32) is overexpressed in two-thirds of gastric cancers. In this report, Zhu and colleagues uncovered a new function for DARPP-32 by demonstrating its role in cancer cell invasion. The results indicate that DARPP-32–CXCR4 interaction stabilizes the CXCR4 protein by attenuating the CXCL-12–induced CXCR4 protein ubiquitination and degradation. The ability of DARPP-32 to bind CXCR4 and activate MT1-MMP/MMP-2 signaling provides a novel mechanism that regulates CXCR4 protein expression and cancer cell invasion.Yi and colleagues found that activated STAT3 increases RANTES expression and secreted RANTES activates STAT3 via an autocrine pathway, which promotes resistance to 4-hydroxytamoxifen. These findings suggest that combination chemotherapy with tamoxifen and a STAT3 or RANTES inhibitor may be a promising treatment for overcoming breast cancer chemoresistance in the clinic. This study therefore provides new insights that may contribute to the proposed autocrine loop of RANTES, in which tamoxifen-resistant breast cancer cells become more aggressive and maintain drug resistance through STAT3 phosphorylation and increased antiapoptotic signals.Recently, histone deacetylase 2 (HDAC2) was reported to be increased in gastric, colon, and liver cancers. However, little is known about the role of HDAC2 in carcinogenesis. The present study discovered that overexpression of HDAC2 was accompanied with the loss of cyclin-dependent kinase inhibitor CDKN2A (p16INK4a). Further studies showed that the expression of p16INK4a was transcriptionally regulated by HDAC2, as demonstrated by the direct binding of HDAC2 on the promoter of p16INK4a. Moreover, inhibition of HDAC2 restored the expression of p16INK4a; induced the apoptosis, autophagic cell death, and cell-cycle arrest in human MKN-1 gastric cancer cells in vitro; and reduced the gastric tumor growth in vivo. These findings provide molecular basis for developing novel therapeutic strategies in gastric cancer through HDAC2 inhibition.SUSD2 (Sushi Domain Containing 2) encodes a membrane surface protein with weak or no expression in normal breast epithelial cells, yet high expression in breast carcinomas. SUSD2 interacts with galectin-1, a secreted protein that promotes tumor immune evasion, angiogenesis, and metastasis. Localization of galectin-1 on the surface of cells is dependent on the presence of SUSD2. Using a syngeneic mouse model, significantly fewer CD4 tumor-infiltrating lymphocytes were present in tumors expressing Susd2 compared with the vector control. SUSD2 contributes to an immune evasion mechanism and may represent a promising therapeutic target for breast cancer.