FoxOs Enforce a Progression Checkpoint to Constrain mTORC1-Activated Renal Tumorigenesis

Gan, Boyi; Lim, Carol S.; Chu, Gerald C.; Hua, Sujun; Ding, Zhihu; Collins, Michael; Hu, Jian; Jiang, Shan; Fletcher-Sananikone, Eliot; Li, Zhuang; Chang, Michelle; Zheng, Hongwu; Wang, Y. Alan; Kwiatkowski, David J.; Kaelin, William G.; Signoretti, Sabina; DePinho, Ronald A.

doi:10.1016/j.ccr.2010.10.019

Cited by 126 publications

(125 citation statements)

References 55 publications

(74 reference statements)

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“…Activation of FOXO3a could function as a tumor suppressor promoting cell-cycle arrest and apoptosis in RCC cell lines (36). In the present study, we found that FOXO3a mRNA levels were dramatically suppressed in primary metastatic ccRCC compared with primary nonmetastatic ccRCC.…”

Section: Discussionsupporting

confidence: 57%

Downregulation of FOXO3a Promotes Tumor Metastasis and Is Associated with Metastasis-Free Survival of Patients with Clear Cell Renal Cell Carcinoma

et al. 2014

Clinical Cancer Research

106

100

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Purpose: To explore the mechanisms underlying clear-cell renal cell carcinoma (ccRCC) metastasis using transcriptional profiling and bioinformatics analysis of ccRCC samples, and to elucidate the role of FOXO3a in ccRCC metastasis.Experimental Design: Gene expression profiling was performed using four primary metastatic and five primary nonmetastatic ccRCC samples. The mRNA and protein levels of FOXO3a in ccRCC samples were investigated by real-time reverse transcription PCR and immunohistochemistry, respectively. The association between metastasis-free survival of patients with ccRCC and FOXO3a mRNA levels was analyzed. Biologic functions of FOXO3a in renal cancer cell lines were investigated. The influence of FOXO3a on tumor metastasis was also studied in vivo orthotopic xenograft tumor model. Finally, the mechanism by which FOXO3a attenuation could increase invasion and migration of tumor cells was explored.Results: Bioinformatics analysis of the profiling data identified FOXO3a as a key factor in ccRCC metastasis. FOXO3a expression was decreased in primary metastatic ccRCC samples. Patients with low FOXO3a mRNA levels had poor metastasis-free survival (P ¼ 0.003). Knocking down FOXO3a induced tumor cell invasion and migration in the nonmetastatic ccRCC cells. Induced FOXO3a overexpression in SN12-PM6 cells could inhibit tumor metastasis in vivo. Downregulation of FOXO3a increased SNAIL1 expression, thereby activating the epithelial-mesenchymal transition (EMT) of RCC cell lines.Conclusions: The loss of FOXO3a induced EMT of tumor cells by upregulating SNAIL1, which promoted tumor cells metastasis in vitro and in vivo. Thus, FOXO3a could be considered as an independent prognostic factor in ccRCC metastasis and could be a marker of occult metastases. Clin Cancer Res; 20(7); 1779-90. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 57%

Downregulation of FOXO3a Promotes Tumor Metastasis and Is Associated with Metastasis-Free Survival of Patients with Clear Cell Renal Cell Carcinoma

et al. 2014

Clinical Cancer Research

106

100

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“…61,62 As PRDM1 is a repressor of MYC transcription, our data implicate a novel mechanism by which FOXO1 downregulates MYC. We further show that MYC represses PRDM1 in cHL.…”

Section: Discussionmentioning

confidence: 89%

FOXO1 repression contributes to block of plasma cell differentiation in classical Hodgkin lymphoma

Vogel

Xie

Guan

et al. 2014

Blood

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Key Points• FOXO1 directly activates PRDM1a, the master regulator of PC differentiation, and it enriches a PC signature in cHL cell lines. • PRDM1a is a tumor suppressor in cHL.The survival of classical Hodgkin lymphoma (cHL) cells depends on activation of NF-kB, JAK/STAT, and IRF4. Whereas these factors typically induce the master regulator of plasma cell (PC) differentiation PRDM1/BLIMP-1, levels of PRDM1 remain low in cHL. FOXO1, playing a critical role in normal B-cell development, acts as a tumor suppressor in cHL, but has never been associated with induction of PC differentiation.Here we show that FOXO1 directly upregulates the full-length isoform PRDM1a in cHL cell lines. We also observed a positive correlation between FOXO1 and PRDM1 expression levels in primary Hodgkin-Reed-Sternberg cells. Further, we show that PRDM1a acts as a tumor suppressor in cHL at least partially by blocking MYC. Here we provide a link between FOXO1 repression and PRDM1a downregulation in cHL and identify PRDM1a as a tumor suppressor in cHL. The data support a potential role for FOXO transcription factors in normal PC differentiation. (Blood. 2014;124(20):3118-3129) IntroductionClassical Hodgkin lymphoma (cHL) differs from other B-cell lymphomas by a unique phenotype of the malignant cells of cHL, Hodgkin and Reed-Sternberg (HRS) cells, characterized by loss of the B-cell program and by the formation of a reactive infiltrate harboring these cells. 1 The repression of the B-cell program in HRS cells is characterized by downregulation of critical B-cell transcription factors, 2 including BCL6. 3 The oncogenic program of cHL is based on the constitutive activation of JAK/STAT, NF-kB, ERK, and PI3K/AKT pathways. [4][5][6][7] Ultimate targets of these pathways are the protooncogenic transcription factors MYC and IRF4. 8,9 Of note, NF-kB, STAT3, and IRF4 converge to induce plasma cell (PC) differentiation in normal B cells by upregulation of the PC master transcription factor PRDM1/BLIMP-1. [10][11][12] Surprisingly, HRS cells express only low levels of PRDM1 and other PC markers. 3,13 PRDM1 acts as a tumor suppressor in diffuse large B-cell lymphoma of the activated B-cell type (ABC-DLBCL), whose oncogenic program resembles that of cHL, including dependency on constitutive NF-kB and JAK-STAT activation and high expression of IRF4. 1,8,14,15 Of note, NF-kB activation in B cells results in the development of lymphomas only when Prdm1 is deleted. 16 We found that FOXO1, which is highly expressed in B cells and in different types of non-Hodgkin lymphoma, is downregulated in cHL. Overexpression of a constitutively active FOXO1 protein induces growth arrest and apoptosis in cHL cell lines.17 FOXO1 belongs to the forkhead box (Fhbox) family of transcription factors that regulates different physiological processes including cell death, differentiation, and oxidative stress.18 FOXO1 plays a central role in the early stages of B-cell differentiation, 19 and it is essential for the expression of B-cell-specific genes such as BCL6, AICDA, an...

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“…Indeed, miRNA-145 has been proposed as a mechanism of epigenic modulation of proliferative and differentiative properties (28,47). A miR-145 reduction was shown in undifferentiated renal tumors in respect to normal renal tissue (13). In embryonic stem cells, miR-145 inhibited Oct4 protein expression.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133⁺progenitors through Oct4/miR-145 balance

Bussolati

Moggio²,

Collino³

et al. 2012

American Journal of Physiology-Renal Physiology

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Low-oxygen tension is an important component of the stem cell microenvironment. In rodents, renal resident stem cells have been described in the papilla, a relatively hypoxic region of the kidney. In the present study, we found that CD133+ cells, previously described as renal progenitors in the human cortex, were enriched in the renal inner medulla and localized within the Henle's loop and thin limb segments. Once isolated, the CD133+ cell population expressed renal embryonic and stem-related transcription factors and was able to differentiate into mature renal epithelial cells. When injected subcutaneously in immunodeficient mice within Matrigel, CD133+ cells generated canalized structures positive for renal specific markers of different nephron segments. Oct4A levels and differentiation potential of papillary CD133+ cells were higher than those of CD133+ cells from cortical tubuli. Hypoxia was able to promote the undifferentiated phenotype of CD133+ progenitors from papilla. Hypoxia stimulated clonogenicity, proliferation, vascular endothelial growth factor synthesis, and expression of CD133 that were in turn reduced by epithelial differentiation with parallel HIF-1α downregulation. In addition, hypoxia downregulated microRNA-145 and promoted the synthesis of Oct4A. Epithelial differentiation increased microRNA-145 and reduced Oct4 level, suggesting a balance between Oct4 and microRNA-145. MicroRNA-145 overexpression in CD133+ cells induced downrelation of Oct4A at the protein level, inhibited cell proliferation, and stimulated terminal differentiation. This study underlines the role of the hypoxic microenvironment in controlling the proliferation and maintaining a progenitor phenotype and stem/progenitor properties of CD133+ cells of the nephron. This mechanism may be at the basis of the maintenance of a CD133+ population in the papillary region and may be involved in renal regeneration after injury.

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FoxOs Enforce a Progression Checkpoint to Constrain mTORC1-Activated Renal Tumorigenesis

Cited by 126 publications

References 55 publications

Downregulation of FOXO3a Promotes Tumor Metastasis and Is Associated with Metastasis-Free Survival of Patients with Clear Cell Renal Cell Carcinoma

Downregulation of FOXO3a Promotes Tumor Metastasis and Is Associated with Metastasis-Free Survival of Patients with Clear Cell Renal Cell Carcinoma

FOXO1 repression contributes to block of plasma cell differentiation in classical Hodgkin lymphoma

Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133⁺progenitors through Oct4/miR-145 balance

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FoxOs Enforce a Progression Checkpoint to Constrain mTORC1-Activated Renal Tumorigenesis

Cited by 126 publications

References 55 publications

Downregulation of FOXO3a Promotes Tumor Metastasis and Is Associated with Metastasis-Free Survival of Patients with Clear Cell Renal Cell Carcinoma

Downregulation of FOXO3a Promotes Tumor Metastasis and Is Associated with Metastasis-Free Survival of Patients with Clear Cell Renal Cell Carcinoma

FOXO1 repression contributes to block of plasma cell differentiation in classical Hodgkin lymphoma

Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133+progenitors through Oct4/miR-145 balance

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Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133⁺progenitors through Oct4/miR-145 balance