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Motor neuron and pancreas homeobox 1/HLXB9 promotes sustained proliferation in bladder cancer by upregulating CCNE1/2.

ABSTRACT: BACKGROUND:Uncontrolled proliferation is thought to be the most fundamental characteristic of cancer. Detailed knowledge of cancer cell proliferation mechanisms would not only benefit understanding of cancer progression, but may also provide new clues for developing novel therapeutic strategies. METHODS:In vitro function of MNX1 (Motor neuron and pancreas homeobox 1) in bladder cancer cell was evaluated using MTT assay, colony formation assay, and bromodeoxyuridine incorporation assay. Real-time PCR and western blotting were performed to detect MNX1 and CCNE1/2 expressions. In vivo tumor growth was conducted in BALB/c-nu mice. RESULTS:We reported that MNX1 is responsible for sustaining bladder cancer cell proliferation. Abnormal MNX1 upregulation in bladder cancer cell lines and 167 human tissue specimens; high MNX1 expression levels correlated significantly with shorter 5-year overall and relapse-free survival in the bladder cancer patients. Furthermore, MNX1 overexpression accelerated bladder cancer cell proliferation and tumorigenicity both in vitro and in vivo, whereas MNX1 downregulation arrested it. In addition, MNX1 transcriptionally upregulated CCNE1 and CCNE2 by directly bounding to their promoters, which promoted G1-S transition in the bladder cancer cells. CONCLUSION:These findings reveal an oncogenic role and novel regulatory mechanism of MNX1 in bladder cancer progression and suggest that MNX1 is a potential prognostic biomarker and therapeutic target.

SUBMITTER: Chen M

PROVIDER: S-EPMC6048799 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Motor neuron and pancreas homeobox 1/HLXB9 promotes sustained proliferation in bladder cancer by upregulating CCNE1/2.

Chen Mingkun M Wu Rongpei R Li Gang G Liu Cundong C Tan Lei L Xiao Kanghua K Ye Yunlin Y Qin Zike Z

Journal of experimental & clinical cancer research : CR 20180716 1

<h4>Background</h4>Uncontrolled proliferation is thought to be the most fundamental characteristic of cancer. Detailed knowledge of cancer cell proliferation mechanisms would not only benefit understanding of cancer progression, but may also provide new clues for developing novel therapeutic strategies.<h4>Methods</h4>In vitro function of MNX1 (Motor neuron and pancreas homeobox 1) in bladder cancer cell was evaluated using MTT assay, colony formation assay, and bromodeoxyuridine incorporation a ...[more]

PMID: 30012177

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Project description:The motor neuron (MN)–hexamer complex consisting of LIM homeobox 3, Islet-1, and nuclear LIM interactor is a key determinant of motor neuron specification and differentiation. To gain insights into the transcriptional network in motor neuron development, we performed a genome-wide ChIP-sequencing analysis and found that the MN–hexamer directly regulates a wide array of motor neuron genes by binding to the HxRE (hexamer response element) shared among the target genes. Interestingly, STAT3-binding motif is highly enriched in the MN–hexamer–bound peaks in addition to the HxRE. We also found that a transcriptionally active form of STAT3 is expressed in embryonic motor neurons and that STAT3 associates with the MN–hexamer, enhancing the transcriptional activity of the MN–hexamer in an upstream signal-dependent manner. Correspondingly, STAT3 was needed for motor neuron differentiation in the developing spinal cord. Together, our studies uncover crucial gene regulatory mechanisms that couple MN–hexamer and STAT-activating extracellular signals to promote motor neuron differentiation in vertebrate spinal cord. To explain our experimental scheme briefly, we are interested in finding target sites for the dimer of transcription factors Isl1 and Lhx3. To mimic the biological activity of Isl1/Lhx3 dimer, we made Isl1-Lhx3 fusion and found that Isl1-Lhx3 has a potent biological activity in multiple systems (i.e. generation of ectopic motor neurons). Then we made ES cell line that induces Flag-tagged Isl1-Lhx3 expression upon Dox treatment. These *mouse* ES cells differentiate to motor neurons (iMN-ESCs) when treated with Dox following EB formation. To identify genomic binding sites of Isl1-Lhx3 (Flag-tagged), we performed ChIP with Flag antibody (pull down of Flag-Isl1-Lhx3) in ES cells treated with Dox. ChIP with Flag antibody in ES cells treated with vehicle (no Dox) was done as a negative control in parallel, and sequenced along with +Dox sample. We have done these experiments twice (two sets).

Dataset Information

Motor neuron and pancreas homeobox 1/HLXB9 promotes sustained proliferation in bladder cancer by upregulating CCNE1/2.

Publications

Motor neuron and pancreas homeobox 1/HLXB9 promotes sustained proliferation in bladder cancer by upregulating CCNE1/2.

Similar Datasets

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