Li W, Wang L, Katoh H, Liu R, Zheng P, Liu YIdentification of a tumor suppressor relay between the FOXP3 and the Hippo pathways in breast and prostate cancers. Cancer Res 71: 2162-2171

Departments of Surgery, Pathology, and Internal Medicine, Division of Immunotherapy, University of Michigan School of Medicine and Cancer Center, Ann Arbor, Michigan 48109, USA.
Cancer Research (Impact Factor: 9.33). 03/2011; 71(6):2162-71. DOI: 10.1158/0008-5472.CAN-10-3268
Source: PubMed


Defective expression of LATS2, a negative regulator of YAP oncoprotein, has been reported in cancer of prostate, breast, liver, brain, and blood origins. However, no transcriptional regulators for the LATS2 gene have been identified. Here we report that spontaneous mutation of the transcription factor FOXP3 reduces expression of the LATS2 gene in mammary epithelial cells. shRNA-mediated silencing of FOXP3 in normal or malignant mammary epithelial cells of mouse and human origin repressed LATS2 expression and increased YAP protein levels. LATS2 induction required binding of FOXP3 to a specific sequence in the LATS2 promoter, and this interaction contributed to FOXP3-mediated growth inhibition of tumor cells. In support of these results, reduced expression and somatic mutations of FOXP3 correlated strongly with defective LATS2 expression in microdissected prostate cancer tissues. Thus, defective expression of LATS2 is attributable to FOXP3 defects and may be a major independent determinant of YAP protein elevation in cancer. Our findings identify a novel mechanism of LATS2 downregulation in cancer and reveal an important tumor suppressor relay between the FOXP3 and HIPPO pathways which are widely implicated in human cancer.

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    • "CRC cell lines did show detectable FOXP3 mRNA signals, although their levels were extremely low when compared to nTregs (Figure 2B). We could not exclude the possibility of that FOXP3 might also function as a potential transcriptional suppressor of oncogene in CRC cells as in breast cancer cells [36-38] and prostate cancer [39,40]. Actually, it has been reported that FOXP3 expression appears widespread in normal epithelia [41] and malignant cells, such as glioblastoma [42], ovarian cancer [43], NSCLC [44], or advanced gastric cancer [45]. "
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    ABSTRACT: Background The influence of natural regulatory T cells (nTregs) on the patients with colon cancer is unclear. Demethylated status of the Treg-specific demethylated region (TSDR) of the FOXP3 gene was reported to be a potential biomarker for the identification of nTregs. Methods The demethylation rate of the TSDR (TSDR-DMR) was calculated by using methylation-specific quantitative polymerase chain reaction (MS-qPCR) assay. The expression of TSDR-DMR and FOXP3 mRNA was investigated in various colorectal cancer cell lines. A total of 130 colon carcinoma samples were utilized to study the DMR at tumor sites (DMRT) and adjacent normal tissue (DMRN). The correlations between DMRs and clinicopathological variables of patients with colon cancer were studied. Results The TSDR-DMRs varied dramatically among nTregs (97.920 ± 0.466%) and iTregs (3.917 ± 0.750%). Significantly, DMRT (3.296 ± 0.213%) was higher than DMRN (1.605 ± 0.146%) (n = 130, p = 0.000). Higher DMRN levels were found in female patients (p = 0.001) and those with distant metastases (p = 0.017), and were also associated with worse recurrence-free survival in non-stage IV patients (low vs. high, p = 0.022). However, further Cox multivariate analysis revealed that the FOXP3-TSDR status does not have prognostic value. Conclusion MS-qPCR assays of FOXP3-TSDR can efficiently distinguish nTregs from non-nTregs. Abnormal recruitment of nTregs occurs in the local tumor microenvironment. Infiltration of tissue-resident nTregs may have a negative role in anti-tumor effects in patients with colon cancer; however, this role is limited and complicated.
    Full-text · Article · Jun 2014 · Molecular Cancer
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    • "Hepatocarcinogenesis is a long-term, complex process involving multiple risk factors and different genetic alterations that occur during initiation, promotion, and progression of the disease [11]. The role of hepatitis B virus (HBV) infection in developing HCC is well accepted, and HBV X protein (HBx) plays critical roles in the development of HCC. "
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    ABSTRACT: Purpose: Yes-associated protein (YAP) and PDZ-binding motif (TAZ) are two important effectors of Hippo pathway controlling the balance of organ size and carcinogenesis. Amphiregulin (AREG) is a member of the epidermal growth factor family, a direct target gene of YAP and TAZ. The role of these proteins in hepatocellular carcinoma (HCC) is unclear. Methods: The expression of YAP, TAZ, and AREG in HCC was analyzed by immunohistochemical staining. The level of secreted serum AREG was also assayed by enzyme-linked immunosorbent (ELISA) assay. Results: YAP, TAZ, and AREG were expressed in 69.2% (27/39), 66.7% (26/39), and 61.5% (24/39) of HCC patients. The expression of YAP was significantly correlated with Edmondson stage (P>0.05), serum AFP level (P>0.05), and HCC prognosis (P>0.05). AREG expression was also significantly correlated with Edmondson stage (P>0.05) and serum AFP level (P>0.05). In addition, the expression of serum AREG was higher than serum AFP in HCC patients. Further multivariate analysis showed that YAP expression was an independent prognostic factor that significantly affected the overall survival of HCC patients. Conclusions: YAP maybe an independent prognostic indicator for HCC patients and serum AREG may be a serological biomarker of HCC.
    Full-text · Article · Apr 2014 · Research Journal of Immunology
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    • "Somatic mutations, deletions, and epigenetic inactivation of FoxP3 are reportedly widespread between human breast and prostate cancers (Liu et al, 2009; Zhang and Sun, 2010; Li et al, 2011), whereas no mutation was found in GC in this study. FoxP3 inhibits cell growth, cell proliferation, migration, and invasion in a lot of cancer cells (Liu et al, 2009; Zhang and Sun, 2010; Li et al, 2011), and inhibits breast and prostate cancer growth by transcriptionally repressing oncogenes HER2 (Zuo et al, 2007), c-Myc (Wang et al, 2009), Skp2 (Zuo et al, 2007), and increasing tumour suppressor gene p21 (Liu et al, 2009). Mice with heterozygous FoxP3 mutations succumbed to spontaneous mammary tumours (Zuo et al, 2007), whereas those with prostatespecific deletions of FoxP3 developed prostate intraepithelial neoplasia (Wang et al, 2009). "
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    ABSTRACT: Background: Forkhead Box P3 (FoxP3) is thought to be a key transcription factor in regulatory T cells (Tregs), and recent data indicate that it is expressed in several tumour cells. However, its precise roles in gastric cancer (GC) and the underlying mechanisms regulating the interaction between GC cells and lymphocytes remain unclear. Methods: FoxP3 expression was examined in tumour cells and Tregs in 150 cases of gastric precancer and cancer, and their prognostic significances were evaluated, respectively, using a tissue microarray containing 135 GC patient samples with a mean 102-month follow-up. FoxP3 involvement in the tumour cells–lymphocytes interaction and its gene function were further investigated. Results: strong cytoplasmic staining of FoxP3 was observed in GC cells. FoxP3 protein expression in tumour cells predicts a good prognosis, whereas high-density Treg predicts a poor prognosis. Moreover, FoxP3 expression in GC cells increased after coculture with peripheral blood mononuclear cells through coculture systems. Upregulation of FoxP3 inhibited tumour growth in tumour-bearing nude mice. Conclusions: High FoxP3 expression in tumour cells predicts better survival in GC, possibility in relation to interaction between tumour cells and lymphocytes in microenvironment. Interfering with FoxP3 expression may open a new therapeutic strategy against tumour progression.
    Full-text · Article · Feb 2014 · British Journal of Cancer
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