microRNA-224 Promotes Cell Proliferation and Tumor Growth in Human Colorectal Cancer by Repressing <i>PHLPP1</i> and <i>PHLPP2</i>

Liao, Wenting; Li, Tingting; Wang, Zheng-Gen; Wang, Shuyang; He, Miao; Ye, Yaping; Lü, Qing; Cui, Yejia; Wu, Ping; Jiao, Hong-Li; Zhang, Chi; Xie, Yi-Jun; Wang, Junxian; Ding, Yan‐Qing

doi:10.1158/1078-0432.ccr-13-0244

Cited by 110 publications

(92 citation statements)

References 37 publications

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“…MicroRNAs (miRNAs) are endogenous non-coding RNAs of ~22 nucleotides, and are evolutionarily conserved (6). They regulate post-transcriptional gene expression through binding to specific regions of target mRNA in a sequence-specific manner (6).…”

Section: Introductionmentioning

confidence: 99%

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miR-448 downregulates MPPED2 to promote cancer proliferation and inhibit apoptosis in oral squamous cell carcinoma

Shen

Liu

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. The incidence of oral squamous cell carcinoma (OSCC) is continuously increasing while its survival rate has not notably improved. There is a pressing need for improved understanding of the genetic regulation of OSCC tumorigenesis and progression. In this study, the function of miR-448 in the regulation of OSCC growth and its putative target were thoroughly analyzed in vitro. The expression of miR-448 was detected in human OSCC specimens and OSCC cell lines (Cal-27 and Scc-9) by reverse transcription-quantitative polymerase chain reaction. The function of miR-448 was investigated in Cal-27 cells transfected with miR-448 inhibitor, and its putative target determined using a luciferase reporter assay. MTT and wound healing assays and flow cytometry were used to evaluate the effects of miR-448 on OSCC proliferation, metastasis and apoptosis. The level of miR-448 was significantly elevated in human OSCC tissues and the Cal-27 cell line. Suppression of miR-448 expression attenuated cell proliferation and migration, and induced apoptosis of Cal-27 cells. Furthermore, miR-448 bound with the 3'-untranslated region of metallophosphoesterase domain containing 2 (MPPED2) mRNA, thereby reducing the MPPED2 protein level. Thus, it appears that miR-448 acts as a tumor inducer, causing OSCC growth by inhibiting the expression of its target MPPED2.These results demonstrate that miR-448 plays a critical role in OSCC tumorigenesis, and is a potential therapeutic target.

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Section: Introductionmentioning

confidence: 99%

“…They regulate post-transcriptional gene expression through binding to specific regions of target mRNA in a sequence-specific manner (6). It is now clear that miRNAs play crucial roles in various biological processes such as differentiation, proliferation, invasion and apoptosis (7).…”

Section: Introductionmentioning

confidence: 99%

miR-448 downregulates MPPED2 to promote cancer proliferation and inhibit apoptosis in oral squamous cell carcinoma

Shen

Liu

et al. 2016

Experimental and Therapeutic Medicine

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“…Although most studies on PHLPP2 have focused on genetic alterations in solid tumors, 8 PHLPP2 protein expression in small cell lung and colorectal cancers is also restricted through translational suppression 9 and post-transcriptional control by microRNAs (miR or miRNAs), miR-205 and miR-224. 10,11 The PHLPP2 3' untranslated region (3'UTR) harbors complementary binding sites for a subset of miRNAs belonging to the miRNA-17-92 cluster. 12 This cluster comprises six miRNAs on chromosome 13, transcribed as a single polycistronic unit.…”

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confidence: 99%

Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17–92 cluster in differentiating AML cells

et al. 2016

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PHLPP2, a member of the PH-domain leucine-rich repeat protein phosphatase (PHLPP) family, which targets oncogenic kinases, has been actively investigated as a tumor suppressor in solid tumors. Little is known, however, regarding its regulation in hematological malignancies. We observed that PHLPP2 protein expression, but not its mRNA, was suppressed in late differentiation stage acute myeloid leukemia (AML) subtypes. MicroRNAs (miR or miRNAs) from the miR-17-92 cluster, oncomir-1, were shown to inhibit PHLPP2 expression and these miRNAs were highly expressed in AML cells that lacked PHLPP2 protein.Studies showed that miR-17-92 cluster regulation was, surprisingly, independent of transcription factors c-MYC and E2F in these cells; instead all-trans-retinoic acid (ATRA), a drug used for terminally differentiating AML subtypes, markedly suppressed miR-17-92 expression and increased PHLPP2 protein levels and phosphatase activity. Finally, we demonstrate that the effect of ATRA on miR-17-92 expression is mediated through its target, transcription factor C/EBPβ, which interacts with the intronic promoter of the miR-17-92 gene to inhibit transactivation of the cluster. These studies reveal a novel mechanism for upregulation of the phosphatase activity of PHLPP2 through C/EBPβ-mediated repression of the miR-17-92 cluster in terminally differentiating myeloid cells. Phosphatases are pivotal components of intracellular signaling cascades, controlling essential processes like metabolism, apoptosis, proliferation and differentiation. 1 The PH-domain leucine-rich repeat protein phosphatase (PHLPP) family serine-threonine phosphatases are emerging as central factors in cell survival and death regulation. The PHLPP2 is a member of this family. 2,3 To date four PHLPP substrates, Akt, PKC, Mst1 and S6K1, have been identified, all kinases involved in cell survival or apoptosis. 4-7 Dephosphorylation inactivates Akt, S6K1 and PKC, and subsequently cell survival signaling, whereas dephosphorylation of Mst1 activates its apoptotic function.PHLPP protein expression and activity is suppressed through various mechanisms in cancers. Although most studies on PHLPP2 have focused on genetic alterations in solid tumors, 8 PHLPP2 protein expression in small cell lung and colorectal cancers is also restricted through translational suppression 9 and post-transcriptional control by microRNAs (miR or miRNAs), miR-205 and miR-224. 10,11 The PHLPP2 3' untranslated region (3'UTR) harbors complementary binding sites for a subset of miRNAs belonging to the miRNA-17-92 cluster. 12 This cluster comprises six miRNAs on chromosome 13, transcribed as a single polycistronic unit. 13,14 Also known as oncomir-1, the cluster enhances cell proliferation or inhibits apoptosis by suppressing targets such as Bim, E2F1 and PTEN and is markedly overexpressed in human cancers. [15][16][17][18][19][20][21] Reduced levels of PHLPP2 in chemoresistant miR-17-92 overexpressing mantle cell lymphomas had suggested that the phosphatase could be a target of oncomir-1. 12 Kno...

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“…In acute promyelocytic leukemia, increased expression of miR125b is involved in the action of current therapeutics (18). In colorectal cancer, upregulating miR224 may increase resistance to methylamine (19). A previous study revealed that NSCLC tissues often possess a deficiency of mixed miR128b (20).…”

Section: Discussionmentioning

confidence: 99%

Epidermal growth factor receptor expression affects proliferation and apoptosis in non-small cell lung cancer cells via the extracellular signal-regulated kinase/microRNA 200a signaling pathway

Zhou

Wang

et al. 2018

Oncol Lett

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Abstract. The present study assessed the function of epidermal growth factor receptor (EGFR) and its molecular targets in non-small cell lung cancer. The results of the present study demonstrated that EGFR protein and mRNA expression in the normal adjacent tissue specimens was decreased compared with that in the lung cancer tissue samples. Compared with the BEAS-2B normal bronchial epithelial cells, EGFR and phosphorylated (p)-extracellular signal-regulated kinase (ERK) protein expression in the SW-900 and A549 lung cancer cells was increased and microRNA (miR)200a expression in the SW-900 and A549 cells was inhibited compared with the BEAS-2B cells. Downregulating miR200a expression significantly suppressed proliferation and promoted apoptosis and caspase (CASP)3 and CASP9 function in the A549 cells and significantly inhibited EGFR and p-ERK protein expression in the A549 cells, compared with the BEAS-2B cells. The results of the present study indicated that downregulating miR200a significantly suppressed proliferation and promoted apoptosis in A549 cells via the regulation of the EGFR and ERK 1/2 signaling pathways. IntroductionLung cancer is a malignant tumor that threatens human health and life, and exhibited the highest global occurrence rate and lethality among all types of cancer in 2012 (1). Its morbidity is increasing in multiple countries (1). At present, the treatment options for patients with lung cancer include surgery, radiotherapy, and chemotherapy. In non-small cell lung cancer (NSCLC), the typical first choice of therapy is operative treatment but, once NSCLC has been definitively diagnosed, surgery is not possible in 75% of patients since lesions have already developed, or the state of their health following surgery would potentially be poorer compared with that prior to surgery (2). Therefore, the patient may opt for chemotherapy. Though chemotherapy may decrease the recurrence rate of NSCLC in patients, only ~30% of patients with NSCLC undergo effective treatment with platinum-based first-line chemotherapy, and chemotherapy resistance is common (3). Furthermore, the 5-year survival rate for patients with NSCLC is only 15% (4). Previous research has indicated that, although novel chemotherapeutics have improved the curative effect in patients with transfer NSCLC, the associated median survival time remains only 8-9 months (5). Therefore, it is crucial to understand the occurrence and development of lung cancer, identify the molecular mechanisms underlying metastasis, and develop effective treatments for patients with malignant lung tumors.The epidermal growth factor receptor (EGFR) family, also known as the Erb-b2 receptor tyrosine kinases (ERBB), includes four main members: EGFR, ERBB2, ERBB3 and ERBB4. The EGFR family members are allosteric enzymes located at the cell surface (3). The members may be divided into three areas: A ligand-coupling domain that protrudes out of the cytomembrane, an intramembrane tyrosine kinase-activated functional domain and a transmembrane domain. The EGFR family...

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microRNA-224 Promotes Cell Proliferation and Tumor Growth in Human Colorectal Cancer by Repressing PHLPP1 and PHLPP2

Cited by 110 publications

References 37 publications

miR-448 downregulates MPPED2 to promote cancer proliferation and inhibit apoptosis in oral squamous cell carcinoma

miR-448 downregulates MPPED2 to promote cancer proliferation and inhibit apoptosis in oral squamous cell carcinoma

Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17–92 cluster in differentiating AML cells

Epidermal growth factor receptor expression affects proliferation and apoptosis in non-small cell lung cancer cells via the extracellular signal-regulated kinase/microRNA 200a signaling pathway

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