Metastasis is the major cause of poor prognosis in colorectal cancer (CRC), and increasing evidence supports the contribution of miRNAs to cancer progression. Here, we found that high expression of miR-103 and miR-107 (miR-103/107) was associated with metastasis potential of CRC cell lines and poor prognosis in patients with CRC. We showed that miR-103/107 targeted the known metastasis suppressors death-associated protein kinase (DAPK) and Kr€ uppel-like factor 4 (KLF4) in CRC cells, resulting in increased cell motility and cell-matrix adhesion and decreased cell-cell adhesion and epithelial marker expression. miR-103/107 expression was increased in the presence of hypoxia, thereby potentiating DAPK and KLF4 downregulation and hypoxiainduced motility and invasiveness. In mouse models of CRC, miR-103/107 overexpression potentiated local invasion and liver metastasis effects, which were suppressed by reexpression of DAPK or KLF4. miR-103/107-mediated downregulation of DAPK and KLF4 also enabled the colonization of CRC cells at a metastatic site. Clinically, the signature of a miR-103/107 high, DAPK low, and KLF4 low expression profile correlated with the extent of lymph node and distant metastasis in patients with CRC and served as a prognostic marker for metastasis recurrence and poor survival. Our findings therefore indicate that miR-103/107-mediated repression of DAPK and KLF4 promotes metastasis in CRC, and this regulatory circuit may contribute in part to hypoxia-stimulated tumor metastasis. Strategies that disrupt this regulation might be developed to block CRC metastasis. Cancer Res; 72(14); 3631-41. Ó2012 AACR.

Activation of metastatic reprogramming is critical for tumour metastasis. However, more detailed knowledge of the underlying mechanism is needed to enable targeted intervention. Here, we show that paraspeckle component 1 (PSPC1), identified in an aberrant 13q12.11 locus, is upregulated and associated with poor survival in patients with cancer. PSPC1 promotes tumorigenesis, epithelial-to-mesenchymal transition (EMT), stemness and metastasis in multiple cell types and in spontaneous mouse cancer models. PSPC1 is the master activator for transcription factors of EMT and stemness and accompanies c-Myc activation to facilitate tumour growth. PSPC1 increases transforming growth factor-β1 (TGF-β1) secretion through an interaction with phosphorylated and nuclear Smad2/3 to potentiate TGF-β1 autocrine signalling. Moreover, PSPC1 acts as a contextual determinant of the TGF-β1 pro-metastatic switch to alter Smad2/3 binding preference from tumour-suppressor to pro-metastatic genes. Having validated the PSPC1-Smads-TGF-β1 axis in various cancers, we conclude that PSPC1 is a master activator of pro-metastatic switches and a potential target for anti-metastasis drugs.

Pulmonary oxygen toxicity plays an important role in the lung injury process that leads to the development of bronchopulmonary dysplasia. Connective tissue growth factor (CTGF) is a fibroblast mitogen and promoter of collagen deposition. We investigated the effects of postnatal hyperoxia on lung collagen and CTGF expression in rats. Rat pups were exposed to 7 d of Ͼ95% O 2 and a further 3 wk of 60% O 2 . CTGF mRNA and protein expression increased after hyperoxia treatment, and the values were significantly higher in hyperoxia-exposed rats on postnatal d 7 and 14. Lung collagen levels increased as rats aged, and the values were comparable between room air-exposed and hyperoxia-exposed rats on postnatal d 7 and 14 and were significantly higher in hyperoxia-exposed rats on postnatal d 21 and 28. Increases in CTGF mRNA and protein expressions preceded the onset of increased lung collagen. These data demonstrate that CTGF is up-regulated at time points preceding the fibrotic phase of the lung injury adding credence to the hypothesis that CTGF seems to be involved in the pathogenesis of hyperoxia-induced lung fibrosis and an anti-CTGF strategy might attenuate hyperoxia-induced lung fibrosis. (Pediatr Res 62: 128-133, 2007)

The TGFb cytokine plays dichotomous roles during tumor progression. In normal and premalignant cancer cells, the TGFb signaling pathway inhibits proliferation and promotes cell-cycle arrest and apoptosis. However, the activation of this pathway in late-stage cancer cells could facilitate the epithelial-to-mesenchymal transition, stemness, and mobile features to enhance tumorigenesis and metastasis. The opposite functions of TGFb signaling during tumor progression make it a challenging target to develop anticancer interventions. Nevertheless, the recent discovery of cellular contextual determinants, especially the binding partners of the transcription modulators Smads, is critical to switch TGFb responses from proapoptosis to prometastasis. In this review, we summarize the recently identified contextual determinants (such as PSPC1, KLF5, 14-3-3z, C/EBPb, and others) and the mechanisms of how tumor cells manage the context-dependent autonomous TGFb responses to potentiate tumor progression. With the altered expression of some contextual determinants and their effectors during tumor progression, the aberrant molecular prometastatic switch might serve as a new class of theranostic targets for developing anticancer strategies.

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide due to metastasis. Paraspeckle component 1 (PSPC1) upregulation has been identified as an HCC pro-metastatic activator associated with poor patient prognosis, but with a lack of targeting strategy. Here, we report that PSPC1, a nuclear substrate of PTK6, sequesters PTK6 in the nucleus and loses its metastasis driving capability. Conversely, PSPC1 upregulation or PSPC1-Y523F mutation promotes epithelial-mesenchymal transition, stemness, and metastasis via cytoplasmic translocation of active PTK6 and nuclear translocation of β-catenin, which interacts with PSPC1 to augment Wnt3a autocrine signaling. The aberrant nucleocytoplasmic shuttling of active PTK6/β-catenin is reversed by expressing the PSPC1 C-terminal interacting domain (PSPC1-CT131), thereby suppressing PSPC1/PTK6/β-catenin-activated metastasis to prolong the survival of HCC orthotopic mice. Thus, PSPC1 is the contextual determinant of the oncogenic switch of PTK6/β-catenin subcellular localizations, and PSPC1-CT131 functions as a dual inhibitor of PSPC1 and PTK6 with potential for improving cancer therapy.

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Cancer stemness drives tumor initiation, progression, metastasis, recurrence, and therapy resistance. However, mechanisms that potentiate the acquisition and maintenance of stemness fate of cancer cells remain incompletely understood. Here, we show that miR-103/107 stimulate multiple stem-like features in colorectal cancer, including expression of stem-like markers, appearance of side-population cells, and capabilities in self-renewal, tumor initiation, recurrence, and chemoresistance. Mechanistically, these stemness-promoting functions are mediated by miR-103/107-dependent repression of Axin2, a negative feedback regulator of Wnt/β-catenin signaling. Through inhibiting Axin2, miR-103/107 trigger a prolonged duration of Wnt/β-catenin signaling and a sustained induction of Wnt responsive genes. In colorectal cancer patients, miR-103/107 expression correlates inversely with Axin2 expression and a signature of miR-103/107 high and Axin2 low expression profile correlates with poor prognosis. Together, our study identifies a novel function of miR-103/107 in promoting colorectal cancer stemness by targeting Axin2 and elucidates the clinical relevance and prognostic value of this axis in colorectal cancer.

Mechanical ventilation with a high tidal volume and no PEEP increases alveolar fibrin deposition and systemic PAI-1 activity, which are attenuated by captopril, an angiotensin-converting enzyme inhibitor. These results imply that local ANG II is involved in the pathogenesis of disordered coagulation in ventilator-induced lung injury (VILI) and suggest that the protective mechanism of captopril's attenuation of VILI is related to a reduction in PAI-1.