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Lili Jiang, Chuyong Lin, Libing Song, Jueheng Wu, Baixue Chen, Zhe Ying, Lishan Fang, Xiao Yan, Mian He, Jun Li, and Mengfeng Li Original citation: J Clin Invest. 2012;122(1):33-47. https://doi.org/10.1172/JCI58849. [...]

Paradoxically, during early tumor development in many cancer types, TGF-[beta] acts as a tumor suppressor, whereas in the advanced stages of these cancers, increased TGF-[beta] expression is linked to high metastasis and poor prognosis. These findings suggest that unidentified mechanisms may function to rewire TGF-[beta] signaling toward its prometastatic role in cancer cells. Our current study using non--small-cell lung carcinoma (NSCLC) cell lines, animal models, and clinical specimens demonstrates that suppression of SMAD2, with SMAD3 function intact, switches TGF-[beta]--induced transcriptional responses to a prometastatic state. Importantly, we identified chaperonin containing TCP1 subunit 6A (CCT6A) as an inhibitor and direct binding protein of SMAD2 and found that CCT6A suppresses SMAD2 function in NSCLC cells and promotes metastasis. Furthermore, selective inhibition of SMAD3 or CCT6A efficiently suppresses TGF-[beta]--mediated metastasis. Our findings provide a mechanism that directs TGF-[beta] signaling toward its prometastatic arm and may contribute to the development of therapeutic strategies targeting TGF-[beta] for NSCLC., Introduction Non--small-cell lung carcinoma (NSCLC) is among the most commonly diagnosed cancers worldwide (1, 2). The prognosis of NSCLC remains poor, and the overall 5-year relative survival rate, including all [...]

JAK2 activity is tightly controlled through a self-inhibitory effect via its JAK homology domain 2 (JH2), which restricts the strength and duration of JAK2/STAT3 signaling under physiological conditions. Although multiple [...]

Tumor metastasis involves a series of biological steps during which the tumor cells acquire the ability to invade surrounding tissues and survive outside the original tumor site. During the early stages, the cancer cells undergo an epithelial-mesenchymal transition (EMT). Wnt/β-catenin signaling is known to drive EMT and metastasis. Here we report that Wnt/β-catenin signaling is hyperactivated in metastatic breast cancer cells that express microRNA 374a (miR-374a). In breast cancer cell lines, ectopic overexpression of miR-374a promoted EMT and metastasis both in vitro and in vivo. Furthermore, miR-374a directly targeted and suppressed multiple negative regulators of the Wnt/β-catenin signaling cascade, including WIF1, PTEN, and WNT5A. Notably, miR-374a was markedly upregulated in primary tumor samples from patients with distant metastases and was associated with poor metastasis-free survival. These results demonstrate that miR-374a maintains constitutively activated Wnt/β-catenin signaling and may represent a therapeutic target for early metastatic breast cancer., Introduction Distant metastasis and invasion of cancer are responsible for more than 90% of cancer-related deaths (1). Biologically, the process of tumor metastasis consists of multiple sequential steps, including invasion [...]

The strength and. d_uration of NF-κB signaling are tightly controlled. by multiple negative feed.back mechanisms. However, in cancer cells, these feed.back loops are overridden through unclear mechanisms to sustain oncogenic activation of NF-κB signaling. Previously, we demonstrated that overexpression of miR-30e* directly represses IKBα expression and lead.s to hyperactivation of NF-κB. Here, we report that miR-182 was overexpressed. in a different set of gliomas with relatively lower miR-30e* expression and. that miR-182 directly suppressed cylindromatosis (CYLD), an NF-κB negative regulator. This suppression of CYLD promoted ubiquitin conjugation of NF-κB signaling pathway components and. induction of an aggressive phenotype of glioma cells both in vitro and. in vivo. Furthermore, we found. that TGF-β induced. miR-182 expression, leading to prolonged. NF-κB activation. Importantly, the results of these experiments were consistent with an identified significant correlation between miR-182 levels with TGF-β hyperactivation and activated. NF-κB in a cohort of human glioma specimens. These findings uncover a plausible mechanism for sustained. NF-κB activation in malignant gliomas and. may suggest a new target for clinical intervention in human cancer., Introduction The NF-κB pathway, serving as a mechanistic link between inflammation and cancer development, is constitutively activated in various types of cancers (1-4). Over the last decade, ubiquitin (Ub) modification [...]

Constitutive activation of NF-κ B is a frequent event in human cancers, playing important roles in cancer development and progression. In nontransformed cells, NF-κ B activation is tightly controlled by I κ Bs. I κ Bs bind NF-κ B in the cytoplasm, preventing it from translocating to the nucleus to modulate gene expression. Stimuli that activate NF-κ B signaling trigger Iκ B degradation, enabling nuclear translocation of NF-κ B. Among the genes regulated by NF-κ B are those encoding the I κ Bs, providing a negative feedback loop that limits NF-κ B activity. How transformed cells override this NF-κ B/I κ B negative feedback loop remains unclear. Here, we report in human glioma cell lines that microRNA-30e* (miR-30e*) directly targets the IκBα 3 -UTR and suppresses IκBα expression. Overexpression of miR-30e* in human glioma cell lines led to hyperactivation of NF-κ B and enhanced expression of NF-κ B-regulated genes, which promoted glioma cell invasiveness in in vitro assays and in an orthotopic xenotransplantation model. These effects of miR-30e* were shown to be clinically relevant, as miR-30e* was found to be upregulated in primary human glioma cells and correlated with malignant progression and poor survival. Hence, miR-30e* provides an epigenetic mechanism that disrupts the NF-κ B/IκBα loop and may represent a new therapeutic target and prognostic marker., Introduction Since its discovery in 1986 (1), NF-κ B has been recognized as one of the most pleiotropic transcription factors and a key player in the regulation of inflammatory and [...]