Itm2a Expression in the Developing Mouse First Lower Molar, and the Subcellular Localization of Itm2a in Mouse Dental Epithelial Cells

Kihara, Makiko; Kiyoshima, Tamotsu; Nagata, Kazuhiro; Wada, Hiroko; Fujiwara, Hiroaki; Hasegawa, Kana; Someya, Hirotaka; Takahashi, Ichiro; Sakai, Hidetaka

doi:10.1371/journal.pone.0103928

Cited by 13 publications

(9 citation statements)

References 32 publications

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“…Some studies supported that ITM2A was associated with cell differentiation, including chondrogenesis, odontogenesis. and myogenesis stages [44][45][46]. A previous study found that ITM2A was markedly downregulated in invasive ovarian carcinomas compared with normal ovarian tissues [47].…”

Section: Discussionmentioning

confidence: 99%

A Five-Genes-Based Prognostic Signature for Cervical Cancer Overall Survival Prediction

Zhao

Huang

Zou

et al. 2020

International Journal of Genomics

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Aims. This study is aimed at identifying a prognostic signature for cervical cancer. Main Methods. The gene expression data and clinical information of cervical cancer and normal cervical tissues were acquired from The Cancer Genome Atlas and from three datasets of the Gene Expression Omnibus database. DESeq2 and Limma were employed to screen differentially expressed genes (DEGs). The overlapping DEGs among all datasets were considered the final DEGs. Then, the functional enrichment analysis was performed. Moreover, the Cox proportional hazards regression was performed to establish a prognostic signature of the DEGs. The Kaplan-Meier analysis was applied to test the model. Relationships between gene expression and clinicopathological parameters in cervical cancer, including age, HPV status, histology, stage, and lymph node metastasis, were analysed by the chi-square test. The somatic mutations of these prognostic genes were assessed through cBioPortal. The robustness of the model was verified in another two independent validation cohorts. Key Findings. In total, 169 overlapping upregulated genes and 29 overlapping downregulated genes were identified in cervical cancer compared with normal cervical tissues. Functional enrichment analysis indicated that the DEGs were mainly enriched in DNA replication, the cell cycle, and the p53 signalling pathway. Finally, a 5-gene- (ITM2A, DSG2, SPP1, EFNA1, and MMP1) based prognostic signature was built. According to this model, each patient was given a prognostic-related risk value. The Kaplan-Meier analysis showed that a higher risk was related to worse overall survival in cervical cancer, with an area under the receiver operating characteristic curve of 0.811 for 15 years. The validity of this model in the prediction of cervical cancer outcome was verified in another two independent datasets. In addition, our study also found that the low expression of ITM2A was associated with cervical adenocarcinoma. Interestingly, DSG2 was associated with the HPV status of cervical cancer. Significance. Our study constructed a prognostic model in cervical cancer and discovered two novel genes, ITM2A and DSG2, associated with cervical carcinogenesis and survival.

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Section: Discussionmentioning

confidence: 99%

A Five-Genes-Based Prognostic Signature for Cervical Cancer Overall Survival Prediction

Zhao

Huang

Zou

et al. 2020

International Journal of Genomics

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“…As ITM2A is downregulated in breast cancer, the inhibitory effect of ITM2A to mTOR could be abolished. It was previously reported that a large amount of GFP-ITM2A was detected in the perinuclear region and mainly localized in the Golgi, with a tiny part of the GFP-ITM2A colocalized with lysosomes [39]. mTORC1 is known to recruit to lysosomes and is activated by the small GTPase RHEB, and RHEB activates lysosome-localized mTORC1 at the Golgi-lysosome contact site [40].…”

Section: Discussionmentioning

confidence: 99%

Integral membrane protein 2A inhibits cell growth in human breast cancer via enhancing autophagy induction

et al. 2019

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Background Breast cancer is a life-threatening disease in females and the leading cause of mortality among the female population, presenting huge challenges for prognosis and treatment. ITM2A is a member of the BRICHOS superfamily, which are thought to have a chaperone function. ITM2A has been identified to related to ovarian cancer progress recently. However, the biological role of ITM2A in breast cancer remains largely unclear. Methods Quantitative real-time polymerase chain reaction (qRT-PCR), western blotting assay and immunohistochemistry staining were used to analyzed the expression level of ITM2A. The patient overall survival versus ITM2A expression level was evaluated by Kaplan-Meier analysis. MTT assay, EdU incorporation assay and colony formation assay were used to evaluated the role of ITM2A on breast cancer cell proliferation. Autophagy was explored through autophagic flux detection using a confocal microscope and autophagic vacuoles investigation under a transmission electron microscopy (TEM). In vitro kinase assay was used to investigated the phosphorylation modification of ITM2A by HUNK. Results Our data showed that the expression of integral membrane protein 2A (ITM2A) was significantly down-regulated in human breast cancer tissues and cell lines. Kaplan-Meier analysis indicated that patients presenting with reduced ITM2A expression exhibited poor overall survival, and expression significantly correlated with age, progesterone receptor status, TNM classification and tumor stage. ITM2A overexpression significantly inhibited the proliferation of breast cancer cells. By studying several autophagic markers and events in human breast cancer SKBR-3 cells, we further demonstrated that ITM2A is a novel positive regulator of autophagy through an mTOR-dependent manner. Moreover, we found that ITM2A was phosphorylated at T35 by HUNK, a serine/threonine kinase significantly correlated with human breast cancer overall survival and HER2-induced mammary tumorigenesis. Conclusion Our study provided evidence that ITM2A functions as a novel prognostic marker and represents a potential therapeutic target. Electronic supplementary material The online version of this article (10.1186/s12964-019-0422-7) contains supplementary material, which is available to authorized users.

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“…The mouse dental epithelial cell line, mDE6, established from mouse tooth germ was kindly provided by Professor Satoshi Fukumoto (Tohoku University, Sendai, Japan). The mDE6 cells were cultured in DMEM/F12 medium supplemented with 10% fetal bovine serum, 100 U/ml penicillin and 100 mg/ml streptomycin (all from Life Technologies, Carlsbad, CA, USA) in a humidified atmosphere of 5% CO 2 at 37°C, as previously described ( 17 , 18 ).…”

Section: Methodsmentioning

confidence: 99%

Thymosin beta 4 is associated with RUNX2 expression through the Smad and Akt signaling pathways in mouse dental epithelial cells

Someya

Fujiwara

Nagata

et al. 2015

International Journal of Molecular Medicine

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In previous studies by our group, we reported that thymosin beta 4 (Tb4) is closely associated with the initiation and development of the tooth germ, and can induce the expression of runt-related transcription factor 2 (RUNX2) during the development of the tooth germ. RUNX2 regulates the expression of odontogenesis-related genes, such as amelogenin, X-linked (Amelx), ameloblastin (Ambn) and enamelin (Enam), as well as the differentiation of osteoblasts during bone formation. However, the mechanisms through which Tb4 induces the expression of RUNX2 remain unknown. In the present study, we employed a mouse dental epithelial cell line, mDE6, with the aim to elucidate these mechanisms. The mDE6 cells expressed odontogenesis-related genes, such as Runx2, Amelx, Ambn and Enam, and formed calcified matrices upon the induction of calcification, thus showing characteristics of odontogenic epithelial cells. The expression of odontogenesis-related genes, and the calcification of the mDE6 cells were reduced by the inhibition of phosphorylated Smad1/5 (p-Smad1/5) and phosphorylated Akt (p-Akt) proteins. Furthermore, we used siRNA against Tb4 to determine whether RUNX2 expression and calcification are associated with Tb4 expression in the mDE6 cells. The protein expression of p-Smad1/5 and p-Akt in the mDE6 cells was reduced by treatment with Tb4-siRNA. These results suggest that Tb4 is associated with RUNX2 expression through the Smad and PI3K-Akt signaling pathways, and with calcification through RUNX2 expression in the mDE6 cells. This study provides putative information concerning the signaling pathway through which Tb4 induces RUNX2 expression, which may help to understand the regulation of tooth development and tooth regeneration.

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Itm2a Expression in the Developing Mouse First Lower Molar, and the Subcellular Localization of Itm2a in Mouse Dental Epithelial Cells

Cited by 13 publications

References 32 publications

A Five-Genes-Based Prognostic Signature for Cervical Cancer Overall Survival Prediction

A Five-Genes-Based Prognostic Signature for Cervical Cancer Overall Survival Prediction

Integral membrane protein 2A inhibits cell growth in human breast cancer via enhancing autophagy induction

Thymosin beta 4 is associated with RUNX2 expression through the Smad and Akt signaling pathways in mouse dental epithelial cells

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