Yujiang Fang

Sirtuin 1 in malignant transformation: Friend or foe?

In the past decade, great interest has been shown in the role of sirtuin 1 (SIRT1) in tumorigenesis. The published data show SIRT1 can function as both a tumor promoter and tumor suppressor. In this review, we summarize the available data regarding the role of SIRT1 in tumorigenesis, with a focus on the potential mechanisms. The seemingly controversial role of SIRT1 in tumorigenesis suggests that SIRT1 might play a dual role in different tissue contexts depending on the temporal and special distribution of different SIRT1 upstream and downstream factors. Clearly, the role of SIRT1 in tumorigenesis is poorly understood and more research is necessary to elucidate its function in the malignant process.

Resveratrol enhances radiation sensitivity in prostate cancer by inhibiting cell proliferation and promoting cell senescence and apoptosis.

Radiation therapy (XRT) for treatment of localized prostate cancer (PCA) has outcomes similar to surgery and medical therapy. Toxicities of XRT and the relative radioresistance of PCA limit the effectiveness of this treatment method. Safe and effective radiosensitizing agents are lacking to enhance the effectiveness for XRT for PCA. In this study, the effect of XRT in combination with the radiosensitizing agent resveratrol (RSV) was investigated in a radioresistant PCA cell line, PC‐3. Our results show the addition of RSV to XRT (XRT/RSV) synergistically enhanced XRT‐induced apoptosis and inhibition of PC‐3 proliferation. The antiproliferative effect of XRT/RSV treatment correlated with increased expression of p15, p21, and mutant p53 and decreased expression of cyclin B, cyclin D, and cdk2. Increased apoptosis correlated with increased expression of Fas and TRAILR1. Furthermore, XRT/RSV had little effect on the expression of p‐AKT, whereas it increased the expression level of p‐H2A.X, a marker for senescence. These data highlight the potential of RSV as a radiation sensitizer for PCA treatment and warrant further investigation. (Cancer Sci 2012; 103: 1090–1098)

The paradoxical role of IL-10 in immunity and cancer

Interleukin-10 (IL-10) produced by a wide-variety of cells is a highly pleiotropic cytokine. It has been implicated in the pathogenesis and/or development of autoimmune diseases and cancer, although it displays differential effects that seem to be contradictory sometimes. The ultimate role of this cytokine in disease, however, cannot be fully determined until the immunological contexts that regulate its function are further elucidated. In this review, we will discuss a wide variety of evidence of IL-10 in immunity and cancer in an effort to illuminate the remaining mysteries in the function of this cytokine that, when fully understood, may prove to be a powerful tool in the battle against cancer.

Comparison of sensitivity of Th1, Th2, and Th17 cells to Fas-mediated apoptosis

Following activation through the TCR, CD4+ T cells can differentiate into three major subsets: Th1, Th2, and Th17 cells. IL‐17‐secreting Th17 cells play an important role in the pathogenesis of several autoimmune diseases and in immune responses to pathogens, but little is known about the regulation of apoptosis in Th17 cells. In this study, the sensitivity of in vitro‐polarized Th1, Th2, and Th17 cells to Fas‐mediated apoptosis was compared directly by different methods. The order of sensitivity of T cell subsets to Fas‐mediated apoptosis is: Th1 > Th17 > Th2. The greater sensitivity of Th17 cells to Fas‐mediated apoptosis compared with Th2 cells correlated with their higher expression of FasL and comparable expression of the antiapoptotic molecule FLIP. The decreased sensitivity of Th17 compared with Th1 cells correlated with the higher expression of FLIP by Th17 cells. Transgenic overexpression of FLIP in T cells protected all three subsets from Fas‐mediated apoptosis. These findings provide new knowledge for understanding how survival of different subsets of T cells is regulated.

The role of IL-11 in immunity and cancer

Interleukin-11 (IL-11) is a member of the glycoprotein-130 (GP-130) cytokines that utilizes the GP-130 signaling pathway shared by other cytokines of the same family. Traditionally regarded as an anti-inflammatory cytokine, IL-11 also demonstrates its role as a proinflammatory cytokine, suggesting its complex role in immune response. In recent years, IL-11 has an emerging role in various inflammation-associated cancers. In this review, we aim to discuss IL-11 signaling pathway, to explore the role of IL-11 in immunity and various cancers, and to provide a therapeutic perspective of strategies utilized to interfere IL-11 signaling in cancer cells.

A critical role for TRAIL in resolution of granulomatous experimental autoimmune thyroiditis

Granulomatous experimental autoimmune thyroiditis (G‐EAT) is induced by mouse thyroglobulin (MTG)‐sensitized splenocytes activated in vitro with MTG and IL‐12. Thyroid lesions reach maximal severity 20 days after cell transfer, and usually resolve or progress to fibrosis by day 60 depending on the extent of thyroid damage at day 20. Our previous studies indicated that neutralization of TNF‐α or FasL had no effect on G‐EAT induction, but neutralization of TNF‐α promoted, while neutralization of FasL inhibited, G‐EAT resolution. TNF‐related apoptosis‐inducing ligand (TRAIL) is a member of the TNF superfamily. This study was undertaken to define the role of endogenous TRAIL in G‐EAT development and/or resolution. Neutralization of endogenous TRAIL had little effect on G‐EAT induction, but significantly inhibited G‐EAT resolution and increased thyroid fibrosis. This correlated with higher expression of pro‐inflammatory cytokines and preferential expression of the pro‐apoptotic molecule TRAIL, and anti‐apoptotic molecules FLIP and Bcl‐xL on inflammatory cells in thyroids of anti‐TRAIL‐treated recipients. The results suggest that endogenous TRAIL is not required for G‐EAT development in recipients, but is critical for G‐EAT resolution. Endogenous TRAIL might promote resolution, at least in part, through modulation of the balance between pro‐ and anti‐inflammatory cytokines, and the expression pattern of pro‐ and anti‐apoptotic molecules of thyroid epithelial cells (TECs) and inflammatory cells. Copyright

A Possible Role for Perforin and Granzyme B in Resveratrol‐Enhanced Radiosensitivity of Prostate Cancer

Perforin and granzyme B are expressed primarily by activated lymphocytes (cytotoxic T cells, natural killer cells, and natural killer T cells) and function together to induce apoptosis of target cells. Typically, these proteins are not expressed in tumor cells. In the present study, we established the constitutive expression of perforin and granzyme B by the PC-3 and DU145 prostate cancer (PCA) cell lines with reverse transcription polymerase chain reaction, immunohistochemistry, Western blot, or a combination of techniques. The combination of radiation and resveratrol (XRT/RSV) additively/synergistically decreased survival of PCA because, at least in part, of increased apoptosis. We further demonstrated that treatment with RSV up-regulated the expression of both perforin and granzyme B, whereas treatment with XRT up-regulated the expression of granzyme B, but not that of perforin. Combined XRT/RSV treatment of PCA cells further increased the expression of both perforin and granzyme B compared with RSV or XRT alone. Thus, increased radiosensitivity of prostate cancer cells induced by RSV correlated with up-regulation of perforin and granzyme B, demonstrating a possible mechanism for tumor apoptosis. These findings might be helpful in devising new strategies for treating PCA.

Interleukin-10 Promotes Resolution of Granulomatous Experimental Autoimmune Thyroiditis

Granulomatous experimental autoimmune thyroiditis (G-EAT) is induced by mouse thyroglobulin-sensitized splenocytes activated in vitro with mouse thyroglobulin and interleukin (IL)-12. Thyroid lesions reach maximal severity 20 days after cell transfer, and inflammation either resolves or progresses to fibrosis by day 60 depending on the extent of thyroid damage at day 20. Depletion of CD8(+) T cells inhibits G-EAT resolution. Our previous studies indicated that IL-10 was generally higher in G-EAT thyroids that resolved. Using both wild-type and IL-10(-/-) CBA/J mice, this study was undertaken to determine whether G-EAT resolution would be inhibited in the absence of IL-10. The results showed that either depletion of CD8(+) T cells or IL-10 deficiency increased fibrosis and inhibited resolution of inflammation. We also found a correlation between higher expression levels of proinflammatory cytokines and preferential expression levels of proapoptotic molecules, such as FasL and TRAIL, and antiapoptotic molecules, such as FLIP and Bcl-xL, in inflammatory cells from thyroids of both CD8-depleted and IL-10-deficient mice. Furthermore, many of the CD8(+) T cells were also IL-10(+). These results suggest that IL-10 plays an important role in G-EAT resolution and might promote resolution, at least in part, through its production in CD8(+) T cells. Further understanding of the mechanisms that promote the resolution of inflammation will facilitate the development of novel strategies for treating autoimmune diseases.

IL-35 promotes pancreas cancer growth through enhancement of proliferation and inhibition of apoptosis: Evidence for a role as an autocrine growth factor

Interleukin-35 (IL-35), an IL-12 cytokine family member, mediates the immune inhibitory function of regulatory T cells (Treg). We assayed the presence of IL-35 in paraffin-embedded human pancreas cancer (PCAN) and unexpectedly found IL-35 was expressed mainly by epithelial derived PCAN cells, but not by Treg. We further examined the expression and effect of exogenous IL-35 in human PCAN cell lines and found IL-35 promoted growth and inhibited apoptosis in PCAN cell lines. IL-35 induced proliferation correlated with an increase in cyclin B, cyclin D, cdk2, and cdk4 and a decrease in p27 expression, while inhibition of apoptosis was associated with an increase in Bcl-2 and a decrease in TRAILR1. We conclude IL-35 is produced by PCAN in vivo and promotes PCAN cell line growth in vitro. These results might indicate an important new role for IL-35 as an autocrine growth factor in PCAN growth.

TGF-β Promotes Proliferation of Thyroid Epithelial Cells in IFN-γ−/− Mice by Down-Regulation of p21 and p27 via AKT Pathway

IFN-γ(-/-) NOD.H-2h4 mice develop an autoimmune disease characterized by hyperplasia and proliferation of thyroid epithelial cells (TEC H/P). Proliferating TECs produce TGF-β, and IFN-γ inhibits TEC H/P. In the present study, cultured TECs were used to directly determine the mechanisms by which these cytokines act on TECs to result in proliferation or inhibition of proliferation. With TECs from IFN-γ(-/-) NOD.H-2h4 mice or mice expressing the dominant negative TGF-β type II receptor on TECs, TGF-β was shown to promote TEC proliferation and IFN-γ was shown to inhibit TEC proliferation in vitro. TGF-β may promote TEC proliferation by down-regulating antiproliferative molecules p21 and p27, whereas IFN-γ may inhibit proliferation by up-regulating antiproliferative molecules p18 and p21 and down-regulating the pro-proliferative molecule cyclin D. Inhibition of AKT abolished the effect of TGF-β on p21 and p27, resulting in similar proliferation of TGF-β-treated and control TECs. Increased expression of proliferating cell nuclear antigen (PCNA), TGF-β, and p-AKT and decreased expression of p21 and p27 by proliferating TECs correlated with the proliferative state of TEC H/P. Taken together, the results suggest that TGF-β promotes TEC proliferation by down-regulating p21 and p27 via the AKT pathway in IFN-γ(-/-) NOD.H-2h4 mice, which may have significant implications for development of effective therapeutic strategies targeting the TGF-β and AKT pathways for treatment of hyperplasia and/or neoplasia.