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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. [...]

Simple Summary: Metastasis, the hallmark of cancer, is accountable for about 90% of cancer-related deaths. Long noncoding RNA (lncRNA), a subset of the noncoding RNAs, has exhibited involvement in various processes, including immune evasion, cell proliferation, migration, and invasion, across multiple human diseases, notably cancer. The objective of our study was to identify a metastasis-associated lncRNA in lung cancer and elucidate the underlying mechanisms. Our findings indicate that Linc01703, which is notably downregulated in metastatic lung cancer cells, effectively suppresses lung cancer metastasis in vivo. Interestingly, Linc01703 does not directly impact the proliferation and invasion capabilities of lung cancer cells but rather inhibits cancer metastasis by promoting the secretion of CD81+ exosomes through the Rab27a/SYTL1/CD81 transport complexes. Consequently, our observations provide new insights into the potential clinical application of CD81+ exosome-based cancer therapy. Metastasis, a major cause of cancer-related mortality worldwide, frequently occurs early in the diagnosis of lung adenocarcinoma (LUAD). However, the precise molecular mechanisms governing the aggressive metastatic behavior of LUAD remain incompletely understood. In this study, we present compelling evidence indicating that the long noncoding RNA linc01703 is significantly downregulated in metastatic lung cancer cells. Intriguingly, in vivo experiments revealed that Linc01703 exerted a profound inhibitory effect on lung cancer metastasis without discernible impact on the in vitro proliferation or invasion capacities of LUAD cells. Mechanistically, Linc01703 enhanced the interaction between Rab27a, SYTL1, and CD81, consequently promoting the secretion of CD81+ exosomes. These exosomes, in turn, suppressed the infiltration of immune cells within the tumor microenvironment, thereby impeding LUAD metastasis. Importantly, our analysis of lung cancer tissues revealed a correlation between reduced CD81 expression and an unfavorable patient prognosis. Collectively, our findings suggest that Linc01703 functions as a metastasis suppressor by facilitating the secretion of CD81+ exosomes through the formation of the Rab27a/SYTL1/CD81 complex. [ABSTRACT FROM AUTHOR]

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 [...]

The importance of mRNA N6‐methyladenosine (m6A) modification during tumor metastasis is controversial as it plays distinct roles in different biological contexts. Moreover, how cancer cell plasticity is shaped by m6A modification is interesting but remains uncharacterized. Here, this work shows that m6A reader insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) is remarkably upregulated in metastatic lung adenocarcinoma (LUAD) and indicates worse prognosis of patients. Interestingly, IGF2BP3 induces partial epithelial‐mesenchymal‐transition (EMT) and confers LUAD cells plasticity to metastasize through m6A‐dependent overactivation of Notch signaling. Mechanistically, IGF2BP3 recognized m6A‐modified minichromosome maintenance complex component (MCM5) mRNAs to prolong stability of them, subsequently upregulating MCM5 protein, which competitively inhibits SIRT1‐mediated deacetylation of Notch1 intracellular domain (NICD1), stabilizes NICD1 protein and contributes to m6A‐dependent IGF2BP3‐mediated cellular plasticity. Notably, a tight correlation of the IGF2BP3/MCM5/Notch axis is evidenced in clinical LUAD specimens. Therefore, this study elucidates a critical role of m6A modification on LUAD cell plasticity in fostering tumor metastasis via the above axis, providing potential targets for metastatic LUAD. [ABSTRACT FROM AUTHOR]

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 [...]

Simple Summary: We show that CLU, especially cytoplasmic precursor CLU, is downregulated in lung cancer and correlates with poor survival. The silencing of CLU promotes lung cancer cell migration and invasion, while the overexpression of CLU potently inhibits these phenomena. Interestingly, secretory CLU proteins are slightly decreased in lung cancer tissue and fail to exert similar anti-metastatic effects like cytoplasmic precursor CLU, demonstrating that cytoplasmic precursor CLU is the primary functional isoform of CLU, which exerts the anti-metastatic effects of lung cancer. Mechanistically, cytoplasmic precursor CLU binds ROCK1 to decrease phosphorylation of ERK1/2 by inhibiting the kinase activity of ROCK1, leading to an anti-metastatic effect in lung cancer cells. These findings reveal a novel insight into the function and regulation of cytoplasmic CLU in lung cancer, which might be a potential target for the diagnosis and treatment of metastatic lung cancer. Clusterin (CLU) is a heterodimeric glycoprotein that has been detected in diverse human tissues and implicated in many cellular processes. Accumulating evidence indicates that the expression of secreted CLU correlates with the progression of cancers. However, the molecular mechanisms underlying its tumor-suppressive roles are incompletely uncovered. In this study, we demonstrate that precursor CLU is widely downregulated in lung cancer tissue, in which secretory CLU proteins are slightly decreased. Impressively, overexpressing CLU potently inhibits the migration, invasion and metastasis of lung cancer cells, whereas silencing CLU promotes this behavior; however, it appears that secretory CLU fails to exert similar anti-metastatic effects. Interestingly, the cytoplasmic precursor CLU binds ROCK1 to abrogate the interaction between ROCK1 and ERK and impair ERK activity, leading to the suppression of lung cancer invasiveness. Meanwhile, the expression of CLU was remarkably diminished in lung cancer bone metastasis loci when compared with subcutaneous tumors in the mouse model and hardly detected in the bone metastasis loci of lung cancer patients when compared with the primary. These findings reveal a novel insight into the function and regulation of cytoplasmic CLU in lung cancer, which might be a potential target for the diagnosis and treatment of metastatic lung cancer. [ABSTRACT FROM AUTHOR]