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Previous studies have indicated that inflammatory stimulation represses protein phosphatase 2A (PP2A), a well-known tumor suppressor. However, whether PP2A repression participates in pancreatic cancer progression has not been verified. We used lipopolysaccharide (LPS) and macrophage-conditioned medium (MCM) to establish in vitro inflammation models, and investigated whether inflammatory stimuli affect pancreatic cancer cell growth and invasion PP2A catalytic subunit (PP2Ac)-dependently. Via nude mouse models of orthotopic tumor xenografts and dibutyltin dichloride (DBTC)-induced chronic pancreatitis, we evaluated the effect of an inflammatory microenvironment on PP2Ac expression in vivo. We cloned the PP2Acα and PP2Acβ isoform promoters to investigate the PP2Ac transcriptional regulation mechanisms. MCM accelerated pancreatic cancer cell growth; MCM and LPS promoted cell invasion. DBTC promoted xenograft growth and metastasis, induced tumor-associated macrophage infiltration, promoted angiogenesis, activated the nuclear factor-κB (NF-κB) pathway, and repressed PP2Ac expression. In vitro, LPS and MCM downregulated PP2Ac mRNA and protein. PP2Acα overexpression attenuated JNK, ERK, PKC, and IKK phosphorylation, and impaired LPS/MCM-stimulated cell invasion and MCM-promoted cell growth. LPS and MCM activated the NF-κB pathway in vitro. LPS and MCM induced IKK and IκB phosphorylation, leading to p65/RelA nuclear translocation and transcriptional activation. Overexpression of the dominant negative forms of IKKα attenuated LPS and MCM downregulation of PP2Ac, suggesting inflammatory stimuli repress PP2Ac expression NF-κB pathway-dependently. Luciferase reporter gene assay verified that LPS and MCM downregulated PP2Ac transcription through an NF-κB-dependent pathway. Our study presents a new mechanism in inflammation-driven cancer progression through NF-κB pathway-dependent PP2Ac repression.

Tetraspanin CD151 interacts with laminin-binding integrins (i.e., α3β1, α6β1 and α6β4) and other cell surface molecules to control diverse cellular and physiological processes, ranging from cell adhesion, migration and survival to tissue architecture and homeostasis. Here, we report a novel role of CD151 in maintaining the branching morphogenesis and activity of progenitor cells during the pubertal development of mammary glands. In contrast to the disruption of laminin-binding integrins, CD151 removal in mice enhanced the tertiary branching in mammary glands by 2.4-fold and the number of terminal end buds (TEBs) by 30%, while having minimal influence on either primary or secondary ductal branching. Consistent with these morphological changes are the skewed distribution of basal/myoepithelial cells and a 3.2-fold increase in proliferating Ki67-positive cells. These novel observations suggest that CD151 impacts the branching morphogenesis of mammary glands by upregulating the activities of bipotent progenitor cells. Indeed, our subsequent analyses indicate that upon CD151 removal the proportion of CD24(Hi)CD49f(Low) progenitor cells in the mammary gland increased by 34%, and their proliferating and differentiating activities were significantly upregulated. Importantly, fibronectin, a pro-branching extracellular matrix (ECM) protein deposited underlying mammary epithelial or progenitor cells, increased by7.2-fold. Moreover, there was a concomitant increase in the expression and nuclear distribution of Slug, a transcription factor implicated in the maintenance of mammary progenitor cell activities. Taken together, our studies demonstrate that integrin-associated CD151 represses mammary branching morphogenesis by controlling progenitor cell activities, ECM integrity and transcription program.

The transcription factor Snail not only functions as a master regulator of epithelial-mesenchymal transition (EMT), but also mediates cell proliferation and survival. While previous studies have showed that Snail protects tumor cells from apoptosis through transcriptional repression of PTEN, the specific mechanism remains unclear. In this study, we demonstrated that Snail cooperates with LSD1 to repress PTEN in a PARP1-dependent manner. Upon doxorubicin treatment, Snail becomes tightly associated with PARP1 through its pADPr-binding motif and is subject to poly(ADP-ribosyl)ation. This modification can enhance Snail-LSD1 interaction and promote the recruitment of LSD1 to PTEN promoter, where LSD1 removes methylation on histone H3 lysine 4 for transcription repression. Furthermore, treatment of tumor cells with PARP1 inhibitor AZD2281 can compromise doxorubicin-induced PTEN suppression and enhance the inhibitory effect of doxorubicin. Together, we proposed a tentative drug-resistant mechanism through which tumor cells defend themselves against DNA damage-induced apoptosis. PARP1 inhibitors in combination with DNA damaging reagents might represent a promising treatment strategy targeting tumors with over-activated Snail and LSD1.

The epithelial-mesenchymal transition have begun to attracted many attentions as a potential mechanism for metastasis. The phenotypic changes of increased motility and invasiveness of cancer cells are reminiscent of epithelial-mesenchymal transition (EMT) that associates with the downregulation of E-cadherin. Snail, zinc finger transcription factor, triggers this process by repressing E-cadherin expression. Recently Snail was found to be dually regulated GSK-3beta through protein stability and cellular localization. The involvement of GSK-3beta and beta-Trcp in the regulation of Snail is particular interesting, because these two molecules are also known to involve in the regulation of Wnt and hedgehog pathways that are known to control cell fate and morphogenesis during development and tumorigenesis. Here, we briefly compare these pathways and propose the possibility of cross-talk among these pathways in the regulation of cell adhesion, cell fate, and migration during metastasis.

FBW7 (F-box and WD repeat domain-containing 7, also known as FBXW7, CDC4, AGO and SEL10) is a well-characterized tumor suppressor and is frequently mutated in a variety of cancers. As a substrate recognition component of SCF (which is a complex of SKP1, CUL1 and F-box proteins) type ubiquitin ligase, FBW7 targets several well-known oncoproteins for ubiquitination and degradation, and therefore controls diverse cellular processes, including cell cycle progression, cell proliferation, cell differentiation and maintenance of genomic stability.1 However, the exact mechanism of FBW7-associated tumor suppression remains elusive. Although cyclin E and c-Myc have been identified as targets of FBW7, the downregulation of these two proteins cannot explain the polyploidy problems associated with FBW7 that are observed in many types of cancers. In a recent issue, Teng et al. showed that FBW7 regulated the ubiquitination and degradation of Aurora B, a mitotic checkpoint kinase that plays a critical role in chromosome alignment, segregation and cytokinesis during mitosis.2 Cancer cells frequently exhibit an unusually high level of Aurora B, leading to dysregulated mitosis and resulting in unequal chromosome segregation, which provides a growth advantage to cancer cells.3 Therefore, Aurora B is an attractive target for therapeutic cancer drugs. Teng et al. demonstrated that FBW7 was a negative regulator of Aurora B, and that the expression of FBW7 suppressed Aurora B-mediated cell growth and mitotic deregulation and reduced the percentage of multinucleated cells caused by Aurora B overexpression. By mapping the interaction region for the mutual association in FBW7 and Aurora B, Teng et al. further identified that R465 and R505 residues of WD 40 domain of FBW7 within the binding pockets are necessary for binding to Aurora B.2 Importantly, FBW7 R465 mutations are frequently observed in cancers.4 The mutant FBW7 would not be able to interact with Aurora B and mediate its degradation, which may lead to Aurora B accumulation and mitotic defects, thereby providing a growth advantage. It has been demonstrated that Aurora B is a negative regulator of p53, and it not only phosphorylates p53, leading to enhanced p53 degradation through MDM2-mediated ubiquitination, but also suppresses p53 transcriptional activity and function.5,6 Loss of p53 causes the downregulation of FBW7α.7 Taken together, these findings suggest the existence of a feedback loop between FBW7, Aurora B and p53. Clearly, a fine balance is critical for maintaining correct chromosome segregation and cell progression during mitosis in normal cells. Any signaling that breaks the balance, such as FBW7 mutations, Aurora B elevation or p53 mutations, may cause mitotic catastrophe and accelerate cancer cell growth. The findings of Teng et al. not only shed a new light on the tumor suppressive functions of FBW7 in oncogenesis, but also provide therapeutic strategy for cancer treatment. Figure 1. FBW7-Aurora B-p53 feedback loop regulates cell processes. FBW7 suppresses Aurora B expression through ubiquitination-mediated protein degradation. Loss of FBW7 leads to the accumulation of Aurora B; Aurora B phosphorylates p53 and enhances ...