Highlights of This Issue

Abstract

The let-7 family is one of the first tumor suppressor microRNAs to be identified. However, the underlying mechanism of let-7 in tumor cell migration is still largely unknown. In this study reported by Hu and colleagues, the expression levels of certain let-7 family members were decreased in the breast cancer patients with lymph node metastasis. Subsequent analyses showed that let-7b inhibited actin dynamics and breast cancer cell motility. Bioinformatic and experimental approaches identified a number of let-7b target genes involved in the actin cytoskeleton pathway. Critically, knockdown of these target genes inhibited cellular migration induced by let-7b repression. These data indicate that reconstitution of let-7 expression in tumor cells could provide a novel therapeutic strategy for the treatment of metastatic disease.Chronic inflammation is a risk factor for cancer because the inflammatory cytokine TNF-α is a tumor promoter. To derive oncogenic stimulation from TNF-α, cancer cells must find ways to disable TNF-α–induced necrosis and apoptosis. TNF-α–induced necrosis is inhibited by caspase-8. Because caspase-8 also stimulates apoptosis, cancer cells are left with no choice but to selectively inhibit the proapoptotic activation of caspase-8. Studies using colon cancer cells have identified a selective mechanism whereby constitutive nuclear expression of β-catenin stabilizes retinoblastoma (RB) expression to inhibit the apoptotic activation of caspase-8. This finding establishes RB as a collaborator of nuclear β-catenin for blocking TNF-α–induced apoptosis in colon cancer cells.Malignant rhabdoid tumor (MRT) is a highly aggressive cancer of young children that displays loss of the SMARCB1/hSNF5 gene but not the TP53/p53 gene. Kuwahara and colleagues report that hSNF5 regulated a subset of p53 target genes, including CDKN1A/p21 and PMAIP1/NOXA, consistent with lower NOXA expression in MRT cell lines. They observed that reexpression of hSNF5 modulated SWI/SNF complex levels at the transcriptional start site (TSS) and was followed by RNA polymerase recruitment and activation of transcription initiation. These results suggest that hSNF5 loss may alter transcription at the TSS via epigenetic mechanisms that induce promoter pausing. Furthermore, this study implicates NOXA inactivation as an important consequence of hSNF5 loss. Thus, the apoptotic pathway regulated by NOXA may provide a key target for understanding MRT tumorigenesis and developing more effective therapies.Hempel and colleagues show that the signaling adaptor protein p130Cas (BCAR1), a known Src family kinase substrate involved in cell migration, is a key redox-responsive protein during the metastatic progression of bladder cancer. Increases in endogenous steady-state H2O2 within metastatic cells are accompanied by enhanced p130Cas phosphorylation, membrane recruitment, Crk interaction, and Rac1 activation. Scavenging of H2O2 abrogates redox-dependent p130Cas signaling. The investigators also demonstrate that these changes are likely a consequence of enhanced thiol oxidation of the phosphatase pool, and show dependence on PTPN12 in regulating p130Cas-signaling. This study highlights the fact that subtle changes in the endogenous reactive oxygen species milieu can have profound effects on prometastatic signaling of tumor cells.