LAP2 Is Widely Overexpressed in Diverse Digestive Tract Cancers and Regulates Motility of Cancer Cells

Kim, Hyun-Jung; Hwang, Sun-Hwi; Han, Myoung‐Eun; Baek, Sungmin; Sim, Hey-Eun; Yoon, Sik; Baek, Sun‐Yong; Kim, Bong-Seon; Kim, Jeong‐Hwan; Kim, Seon‐Young; Oh, Sae‐Ock

doi:10.1371/journal.pone.0039482

Cited by 25 publications

(18 citation statements)

References 47 publications

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“…LEM domain proteins play critical roles in DNA replication and regulation of DNA expression. LAP2β, one of LAP2 isoforms, regulates DNA replication in G1 phase of cell cycle by interacting with HA95 protein,24 which was consistent with Kim’s report 13. Here we presented the data demonstrating over-expression of TMPO in lung cancer cells comparing with normal tissues, and down-regulated expression of TMPO inhibited cancer cell growth and invasion ability.…”

Section: Discussionsupporting

confidence: 91%

“…The nucleoplasmic LAP2α has dual functions of either suppressing or promoting proliferation depending on different cellular status 10,11. LAP2α and LAP2β were found to be over-expressed in malignant hematologic diseases,12 digestive tract carcinomas,13 glioblastoma14 and other cancers 11. However, until now, the prognostic value of TMPO in lung cancer has not been studied yet.…”

Section: Introductionmentioning

confidence: 99%

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<p>Prognostic significance and biological function of Lamina-associated polypeptide 2 in non-small-cell lung cancer</p>

Liu

Qiao

et al. 2019

OTT

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Purpose: Lamina-associated polypeptide 2 (LAP2; encoded by TMPO ), is a nuclear protein that may affect chromatin regulation and gene expression through dynamically binding to nuclear lamin. TMPO (LAP2) plays dual roles of either suppressing or promoting proliferation of cells, depending on the status of the cell. It has been reported that TMPO is up-regulated in various cancer types. However, its function in lung cancer has not been studied yet. Materials and methods: A series of clinical microarray datasets for lung cancer were investigated to demonstrate the expression of TMPO. The transcription of TMPO gene in human lung cancer was analyzed using Oncomine platform (www.oncomine.org) according to the standardized procedures described previously. Four separate datasets (Hou Lung, Okayama Lung, Beer Lung, and Garber Lung) were analyzed. Results: Here, we show that TMPO is over-expressed in lung cancer tissues, and that a high level of TMPO indicates a poor prognosis in lung cancer patients. Knockdown of TMPO in lung cancer cells inhibits cell proliferation and induces apoptosis. Also, down-regulation of TMPO leads to an impaired metastatic ability of tumor cells. A nude mice tumor model show that knockdown of TMPO suppresses tumor formation in vivo. Conclusion: Collectively, this study suggests TMPO as an oncogene and a novel prognostic gene in lung cancer.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

<p>Prognostic significance and biological function of Lamina-associated polypeptide 2 in non-small-cell lung cancer</p>

Liu

Qiao

et al. 2019

OTT

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“…The role of TMPOP2 in the development of other cancers is worth further study. TMPO (thymopoietin), also named LAP2 (lamina-associated polypeptide 2), is a conserved nuclear protein important for nuclear assembly and is overexpressed in various tumors (32)(33)(34). TMPOP2 is a pseudogene of TMPO/LAP2.…”

Section: Discussionmentioning

confidence: 99%

Human Papillomavirus E6/E7 and Long Noncoding RNA TMPOP2 Mutually Upregulated Gene Expression in Cervical Cancer Cells

Liu

et al. 2019

J Virol

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TMPOP2 was previously suggested to be an oncogenic long noncoding RNA which is excessively expressed in cervical cancer cells and inhibits E-cadherin gene expression by recruiting transcription repressor EZH2 to the gene promoter. So far, the function and regulation of TMPOP2 in cervical cancer remain largely unknown. Herein, we found that TMPOP2 expression was correlated with human papillomavirus 16/18 (HPV16/18) E6 and E7 in cervical cancer cell lines CaSki and HeLa. Tumor suppressor p53, which is targeted for degradation by HPV16/18, was demonstrated to associate with two p53 response elements in the TMPOP2 promoter to repress the transcription of the TMPOP2 gene. Reciprocally, ectopic expression of TMPOP2 was demonstrated to sequester tumor repressor microRNAs (miRNAs) miR-375 and miR-139 which target HPV16/18 E6/E7 mRNA and resulted in an upregulation of HPV16/18 E6/E7 genes. Thereby, HPV16/18 E6/E7 and the long noncoding RNA (lncRNA) TMPOP2 form a positive feedback loop to mutually derepress gene expression in cervical cancer cells. Moreover, results of RNA sequencing and cell cycle analysis showed that knockdown of TMPOP2 impaired the expression of cell cycle genes, induced cell cycle arrest, and inhibited HeLa cell proliferation. Together, our results indicate that TMPOP2 and HPV16/18 E6/E7 mutually strengthen their expression in cervical cancer cells to enhance tumorigenic activities. IMPORTANCE Human papillomaviruses 16 and 18 (HPV16/18) are the main causative agents of cervical cancer. Viral proteins HPV16/18 E6 and E7 are constitutively expressed in cancer cells to maintain oncogenic phenotypes. Accumulating evidences suggest that HPVs are correlated with the deregulation of long noncoding RNAs (lncRNAs) in cervical cancer, although the mechanism was unexplored in most cases. TMPOP2 is a newly identified lncRNA excessively expressed in cervical cancer. However, the mechanism for the upregulation of TMPOP2 in cervical cancer cells remains largely unknown and its relationship with HPVs is still elusive. The significance of our research is in revealing the mutual upregulation of HPV16/18 E6/E7 and TMPOP2 with the molecular mechanisms explored. This study will expand our understandings of the oncogenic activities of human papillomaviruses and lncRNAs. KEYWORDS HPV E6/E7, cervical cancer, lncRNA TMPOP2, miRNAs, p53 H igh-risk human papillomaviruses (HPVs), primarily including HPV16 and HPV18, are causative agents of cervical cancer, which is one of the leading lethal female cancers worldwide. Integration of HPV DNA into the host cell genome results in the constitutive high expression of two viral oncogenes, HPV E6 and E7, under the control of cellular transcription factors. Viral protein E6 promotes p53 protein degradation FIG 4 TMPOP2 reciprocally regulated the expression of HPV E6/E7 in cervical cancer cells. (A) The efficacy of TMPOP2 knockdown in HeLa cells. (B)The protein levels of HPV18 E6/E7 were decreased following TMPOP2 knockdown. GAPDH was the protein loading control. (C) The mRNA levels of HPV1...

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“…TMPO has been identified as an oncogene in several types of cancer, including breast cancer, lung cancer and glioblastoma (22). Specifically, the regulation of cell motility, proliferation, cell cycle distribution and apoptosis have been described for TMPO in a various types of digestive tract cancer, glioblastoma and/or other types of cancer (22,23). However, whether TMPO serves an important role in PDAC and is regulated by miR-139-5p remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of thymopoietin by miR‑139‑5p suppresses cell proliferation and induces cell cycle arrest/apoptosis in pancreatic ductal adenocarcinoma

Zhou

Zhang

2019

Oncol Lett

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MicroRNAs (miRNAs) serve a pivotal role in tumor development and progression, in which miRNA (miR)-139-5p functions as a tumor suppressor. However, the functions and mechanisms of miR-139-5p in pancreatic ductal adenocarcinoma (PDAC) remain unclear. In the present study, it was found that miR-139-5p was markedly decreased in PDAC tissues and cell lines. Noticeably, thymopoietin (TMPO) was predicted and confirmed as a direct target of miR-139-5p using a luciferase reporter system. The expression level of miR-139-5p was inversely associated with the expression of TMPO in PDAC specimens. A series of gain-of-function assays elucidated that the overexpression of miR-139-5p suppressed cell proliferation, and induced cell cycle arrest and cell apoptosis, determined with a Cell Counting Kit-8, colony formation assays and flow cytometry, respectively. Furthermore, the re-expression of TMPO eliminated the effects of miR-139-5p on cell proliferation, cell cycle progression and apoptosis. In summary, these findings demonstrated that miR-139-5p may be a tumor suppressor in PDAC, which may be useful in developing promising therapies for PDAC.

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LAP2 Is Widely Overexpressed in Diverse Digestive Tract Cancers and Regulates Motility of Cancer Cells

Cited by 25 publications

References 47 publications

<p>Prognostic significance and biological function of Lamina-associated polypeptide 2 in non-small-cell lung cancer</p>

<p>Prognostic significance and biological function of Lamina-associated polypeptide 2 in non-small-cell lung cancer</p>

Human Papillomavirus E6/E7 and Long Noncoding RNA TMPOP2 Mutually Upregulated Gene Expression in Cervical Cancer Cells

Downregulation of thymopoietin by miR‑139‑5p suppresses cell proliferation and induces cell cycle arrest/apoptosis in pancreatic ductal adenocarcinoma

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