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Simple Summary: Bladder cancer ranks fourth among the most prevalent cancers in men and is the most expensive cancer to treat on a per-patient basis. The muscle-invasive form of bladder cancer is one of the deadliest cancers, with a 5-year survival rate of only 6% in patients with distant metastasis. Effective therapeutic options remain few and far between. SNHG1 is a long non-coding RNA that is over-expressed in 95% of muscle-invasive bladder cancers. However, very little information is available about the role and mechanisms of SNHG1 in bladder tumor formation and progression. Here, we provide experimental evidence establishing that SNHG1 drives bladder cancer cell invasion and stem-cell-like behaviors through a specific signaling pathway. Our results reveal novel biomarkers predictive of the progression of muscle-invasive bladder cancer and potential new targets for therapeutic intervention. The stem-cell-like behavior of cancer cells plays a central role in tumor heterogeneity and invasion and correlates closely with drug resistance and unfavorable clinical outcomes. However, the molecular underpinnings of cancer cell stemness remain incompletely defined. Here, we show that SNHG1, a long non-coding RNA that is over-expressed in ~95% of human muscle-invasive bladder cancers (MIBCs), induces stem-cell-like sphere formation and the invasion of cultured bladder cancer cells by upregulating Rho GTPase, Rac1. We further show that SNHG1 binds to DNA methylation transferase 3A protein (DNMT3A), and tethers DNMT3A to the promoter of miR-129-2, thus hyper-methylating and repressing miR-129-2-5p transcription. The reduced binding of miR-129-2 to the 3′-UTR of Rac1 mRNA leads to the stabilization of Rac1 mRNA and increased levels of Rac1 protein, which then stimulates MIBC cell sphere formation and invasion. Analysis of the Human Protein Atlas shows that a high expression of Rac1 is strongly associated with poor survival in patients with MIBC. Our data strongly suggest that the SNHG1/DNMT3A/miR-129-2-5p/Rac1 effector pathway drives stem-cell-like and invasive behaviors in MIBC, a deadly form of bladder cancer. Targeting this pathway, alone or in combination with platinum-based therapy, may reduce chemoresistance and improve longer-term outcomes in MIBC patients. [ABSTRACT FROM AUTHOR]

BACKGROUNG: Long-term exposure of arsenite leads to human skin cancer. However, the exact mechanisms of arsenite-induced human skin carcinogenesis remain to be defined. OBJECTIVES: In this study, we investigated the [...]

BACKGROUND: Arsenic contamination has become a major public health concern worldwide. Epidemiologic data show that long-term arsenic exposure results in the risk of skin cancer. However, the mechanisms underlying carcinogenic [...]

Cross talk between NF-[kappa]B and c-Jun N-terminal kinases (JNKs) has been implicated in the cell life and death decision under various stresses. Functional suppression of JNK activation by NF-[kappa]B has recently been proposed as a key cellular survival mechanism and contributes to cancer cells escaping from apoptosis. We provide a novel scenario of the proapoptotic role of I[kappa]B kinase [beta] (IKK[beta])-NF-[kappa]B, which can act as the activator of the JNK pathway through the induction of GADD45[alpha] for triggering MKK4/JNK activation, in response to the stimulation of arsenite, a cancer therapeutic reagent. This effect of IKK[beta]NF-[kappa]B is dependent on p50 but not the p65/relA NF-[kappa]B subunit, which can increase the stability of GADD45[alpha] protein through suppressing its ubiquitination and proteasome-dependent degradation. IKK[beta]-NF-[kappa]B can therefore either activate or suppress the JNK cascade and consequently mediate pro- or antiapoptotic effects, depending on the manner of its induction. Furthermore, the NF-[kappa]B p50 subunit can exert a novel regulatory function on protein modification independent of the classical NF-[kappa]B transcriptional activity.

Occupational exposure to crystalline silica has been associated with progressive pulmonary silicosis and lung cancer, but the underlying molecular mechanisms are not well understood. Previous studies have shown that crystalline silica exposure can generate reactive oxygen species (ROS) and induce the expression of the inflammatory cytokine tumor necrosis factor-[alpha] (TNF-[alpha]) in cells. TNF-[alpha] is believed to be critical in the development of silica-related diseases. Thus it will be of significance to understand the mechanisms of TNF-[alpha] induction by silica exposure. Given the fact that the transcription factor nuclear factor of activated T cells (NFAT) plays an important role in the regulation of TNF-[alpha] and can also be activated by ROS, in this study we investigated the potential role of ROS in silica-induced NFAT activity as well as TNF-[alpha] expression in C141 cells. The results showed that exposure of cells to silica led to NFAT transactivation and TNF-[alpha] induction, where superoxide anion radical ([O.sup.-.sub.2]*), but not [H.sub.2][O.sub.2], was involved. The knockdown of NFAT3 by its specific small interfering RNA significantly attenuated the silica-induced TNF-[alpha] transcription. This study demonstrated that silica was able to activate NFAT in an [O.sup.-.sub.2]*-dependent manner, which was required for TNF-[alpha] induction. silica; nuclear factor of activated T cells; tumor necrosis factor-[alpha]; reactive oxygen species; signal transduction doi:10.1152/ajplung.00007.2006