MicroRNA-224 inhibits progression of human prostate cancer by downregulating TRIB1

Lin, Zhengfang; Huang, Yaqiang; Zhang, Yanqiong; Han, Zhengxue; He, Hui‐Chan; Ling, Xuemei; Fu, Xin; Dai, Qi-Shan; Cai, Chao; Chen, Jiahong; Liang, Yu‐Xiang; Jiang, Funeng; Zhong, Weide; Wang, Fen; Wu, Chin‐Lee

doi:10.1002/ijc.28707

Cited by 93 publications

(107 citation statements)

References 48 publications

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“…It has been reported that miR-224 was up-regulated in a number of solid tumors, including hepatocellular carcinoma (31,32), CRC (33), and breast cancer (34), and plays an oncogenic role by targeting API5, SMAD4, PHLPP1, PHLPP2, and RKIP. Inversely, miR-224 plays a tumor-suppressive role in prostate cancer by targeting TPD52 and/or TRIB1 (35,36).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-224 promotes tumor progression in nonsmall cell lung cancer

Cui

Wang

Sun

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

133

130

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Lung cancer is the leading cause of cancer-related deaths worldwide. Despite advancements and improvements in surgical and medical treatments, the survival rate of lung cancer patients remains frustratingly poor. Local control for early-stage nonsmall cell lung cancer (NSCLC) has dramatically improved over the last decades for both operable and inoperable patients. However, the molecular mechanisms of NSCLC invasion leading to regional and distant disease spread remain poorly understood. Here, we identify microRNA-224 (miR-224) to be significantly up-regulated in NSCLC tissues, particularly in resected NSCLC metastasis. Increased miR-224 expression promotes cell migration, invasion, and proliferation by directly targeting the tumor suppressors TNFα-induced protein 1 (TNFAIP1) and SMAD4. In concordance with in vitro studies, mouse xenograft studies validated that miR-224 functions as a potent oncogenic miRNA in NSCLC in vivo. Moreover, we found promoter hypomethylation and activated ERK signaling to be involved in the regulation of miR-224 expression in NSCLC. Up-regulated miR-224, thus, facilitates tumor progression by shifting the equilibrium of the partially antagonist functions of SMAD4 and TNFAIP1 toward enhanced invasion and growth in NSCLC. Our findings indicate that targeting miR-224 could be effective in the treatment of certain lung cancer patients.ung cancer is the second most common cancer and the leading cause of cancer-related death worldwide. In 2013, there were an estimated 228,190 new cases of lung cancer and 159,480 deaths in the United States. Despite advancements and improvements in surgical and medical treatments, the 5-y survival rate of lung cancer patients remains frustratingly poor (1). Although local control for early-stage nonsmall cell lung cancer (NSCLC) has dramatically improved over the last decades for both operable and inoperable patients (2, 3), ∼20% of early-stage patients, however, are developing distant metastasis (4, 5), and

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Section: Discussionmentioning

confidence: 99%

MicroRNA-224 promotes tumor progression in nonsmall cell lung cancer

Cui

Wang

Sun

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

133

130

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“…6,7) Importantly, TRB1 is also found to be overexpressed in solid tumors, including prostate cancer, 8,9) thyroid cancer, 10) ovarian cancer, 11) and colorectal cancer. 12) In prostate cancer, Mashima et al have shown that TRB1 is a critical factor for cancer cell stemness and tumor propagating through expression of the endoplasmic reticulum chaperone GRP78.…”

Section: Discussionmentioning

confidence: 99%

“…4,5) TRB1 is also found to be overexpressed in solid tumors, including prostate cancer, 8,9) thyroid cancer, 10) ovarian cancer, 11) and colorectal cancer.…”

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confidence: 99%

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Pseudokinase Tribbles 1 (TRB1) Negatively Regulates Tumor-Suppressor Activity of p53 through p53 Deacetylation

Miyajima

Inoue

Hayashi

2015

Biological & Pharmaceutical Bulletin

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Tribbles 1 (TRB1) is one of the mammalian orthologs of Drosophila Tribbles, which regulates development and cell proliferation. TRB1 is suggested to act as a scaffold protein in signaling pathways for important cellular processes. TRB1 has also been identified as a myeloid oncogenic driver and mediates leukemogenesis through the mitogen-activated protein extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway and CCAAT/enhancer binding protein (C/EBP) transcriptional factors. However, the physiological roles of TRB1 in solid tumors have not been clarified. Here, we show that TRB1 interacts with p53 and suppresses its tumor suppressor activity. TRB1 knockdown enhances transcriptional activity of p53 and decreases cell viability. Interestingly, TRB1 enhances histone deacety lase 1 (HDAC1)-mediated p53 deacetylation and decreases DNA binding of p53. These results suggest that TRB1 is involved in the proliferation of tumor cells by inhibiting the activities of tumor suppressor p53 in solid tumors.Key words Tribbles 1 (TRB1); p53; histone deacetylase 1 (HDAC1); deacetylationThe pseudokinase Tribbles 1 (TRB1; also termed Trib1, C8FW, SKIP1) is one of the mammalian orthologs of Tribbles, a cell cycle regulator during development in Drosophila. 1,2) TRB1 has a conserved motif, which is similar to the catalytic domain of a serine/threonine kinase, but lacks an ATP binding site or one of the conserved catalytic motifs essential for kinase activity.3,4) Therefore, TRB1 is considered as a scaffold protein or an adaptor protein to facilitate the degradation of their target proteins and to regulate several key signaling pathways for important cellular processes.5) In cancer, TRB1 has been identified as a myeloid oncogenic driver and induces acute myeloid leukemia (AML) in mice through the mitogenactivated protein extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway and CCAAT/enhancer binding protein (C/EBP) transcriptional factors.6,7) Importantly, TRB1 is often overexpressed in AML and myelodysplastic syndrome with gene amplification.4,5) TRB1 is also found to be overexpressed in solid tumors, including prostate cancer, 8,9) thyroid cancer, 10) ovarian cancer, 11) and colorectal cancer. 12)Moreover, Oncomine data analyses show that TRB1 is overexpressed in other types of cancer (e.g. breast, esophageal, head and neck, and melanoma). 12) However, whether and how TRB1 plays the physiological roles in solid tumors has not been fully investigated.The tumor suppressor p53 plays an important role in regulating cell proliferation during various stimuli, including genotoxic stress and oncogenic activation, and nearly all cancers show defects in p53 pathway. [13][14][15][16] p53 primarily functions as a transcriptional factor that activates various genes responsible for cell-cycle arrest, senescence or apoptosis to prevent tumor cell growth.17) The expression of p53 is tightly regulated by a mechanism involving the ubiquitin-proteasome-mediated degradation pathway. When cells experienc...

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“…Moreover, TRIB1 is involved in prostate cancer cell survival. Recently, it was reported that the TRIB1 expression was also regulated by a microRNA (miR-224) in prostate cancer and the TRIB1 upregulation was significantly associated with poor biochemical recurrence-free survival of patients with prostate cancer (35). These data suggest that TRIB1 could be a rational therapeutic target in prostate cancer.…”

Section: Trib1 and Grp78 As Therapeutic Targets Of Prostate Cancermentioning

confidence: 94%

TRIB1 Supports Prostate Tumorigenesis and Tumor-Propagating Cell Survival by Regulation of Endoplasmic Reticulum Chaperone Expression

et al. 2014

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Endocrine therapy is the standard treatment for advanced prostate cancer; however, relapse occurs in most patients with few treatment options available after recurrence. To overcome this therapeutic hurdle, the identification of new molecular targets is a critical issue. The capability to proliferate in three-dimensional (3D) conditions is a characteristic property of cancer cells. Therefore, factors that regulate 3D growth are considered rational targets for cancer therapy. Here, we applied a functional genomic approach to the 3D spheroid cell culture model and identified TRIB1, a member of the Trib family of serine/threonine kinase-like proteins, as an essential factor for prostate cancer cell growth and survival. RNAi-mediated silencing of TRIB1 suppressed prostate cancer cell growth selectively under the 3D conditions. This effect was rescued by ectopic expression of an RNAi-resistant TRIB1 exogene. Gene signature-based analysis revealed that TRIB1 was related to endoplasmic reticulum (ER) pathways in prostate cancer and was required for expression of the ER chaperone GRP78, which is critical for prostate tumorigenesis. Of note, GRP78 was expressed preferentially in a subpopulation of prostate cancer cells that possess tumor-propagating potential, and these tumor-propagating cells were highly sensitive to TRIB1 and GRP78 depletion. In a xenograft model of human prostate cancer, TRIB1 depletion strongly inhibited tumor formation. Supporting these observations, we documented frequent overexpression of TRIB1 in clinical specimens of prostate cancer. Overall, our results indicated that the TRIB1-ER chaperone axis drives prostate tumorigenesis and the survival of the tumor-propagating cells. Cancer Res; 74(17); 4888-97. Ó2014 AACR.

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MicroRNA-224 inhibits progression of human prostate cancer by downregulating TRIB1

Cited by 93 publications

References 48 publications

MicroRNA-224 promotes tumor progression in nonsmall cell lung cancer

MicroRNA-224 promotes tumor progression in nonsmall cell lung cancer

Pseudokinase Tribbles 1 (TRB1) Negatively Regulates Tumor-Suppressor Activity of p53 through p53 Deacetylation

TRIB1 Supports Prostate Tumorigenesis and Tumor-Propagating Cell Survival by Regulation of Endoplasmic Reticulum Chaperone Expression

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