Malic Enzyme 1 Is Associated with Tumor Budding in Oral Squamous Cell Carcinomas
Budding at the tumor invasive front has been correlated with the malignant properties of many cancers. Malic enzyme 1 (ME1) promotes the Warburg effect in cancer cells and induces epithelial–mesenchymal transition (EMT) in oral squamous cell carcinoma (OSCC). Therefore, we investigated the role of M...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-09-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/19/7149 |
| _version_ | 1797552344843419648 |
|---|---|
| author | Chie Nakashima Tadaaki Kirita Kazuhiko Yamamoto Shiori Mori Yi Luo Takamitsu Sasaki Kiyomu Fujii Hitoshi Ohmori Isao Kawahara Takuya Mori Kei Goto Shingo Kishi Rina Fujiwara-Tani Hiroki Kuniyasu |
| author_facet | Chie Nakashima Tadaaki Kirita Kazuhiko Yamamoto Shiori Mori Yi Luo Takamitsu Sasaki Kiyomu Fujii Hitoshi Ohmori Isao Kawahara Takuya Mori Kei Goto Shingo Kishi Rina Fujiwara-Tani Hiroki Kuniyasu |
| author_sort | Chie Nakashima |
| collection | DOAJ |
| description | Budding at the tumor invasive front has been correlated with the malignant properties of many cancers. Malic enzyme 1 (ME1) promotes the Warburg effect in cancer cells and induces epithelial–mesenchymal transition (EMT) in oral squamous cell carcinoma (OSCC). Therefore, we investigated the role of ME1 in tumor budding in OSCC. Tumor budding was measured in 96 human OSCCs by immunostaining for an epithelial marker (AE1/AE3), and its expression was compared with that of ME1. A significant correlation was observed between tumor budding and ME1 expression. The correlation increased with the progression of cancer. In human OSCC cells, lactate secretion decreased when lactate fermentation was suppressed by knockdown of ME1 and lactate dehydrogenase A or inhibition of pyruvate dehydrogenase (PDH) kinase. Furthermore, the extracellular pH increased, and the EMT phenotype was suppressed. In contrast, when oxidative phosphorylation was suppressed by PDH knockdown, lactate secretion increased, extracellular pH decreased, and the EMT phenotype was promoted. Induction of chemical hypoxia in OSCC cells by CoCl<sub>2</sub> treatment resulted in increased ME1 expression along with HIF1α expression and promotion of the EMT phenotype. Hypoxic conditions also increased matrix metalloproteinases expression and decreased mitochondrial membrane potential, mitochondrial oxidative stress, and extracellular pH. Furthermore, the hypoxic treatment resulted in the activation of Yes-associated protein (YAP), which was abolished by ME1 knockdown. These findings suggest that cancer cells at the tumor front in hypoxic environments increase their lactate secretion by switching their energy metabolism from oxidative phosphorylation to glycolysis owing to ME1 overexpression, decrease in extracellular pH, and YAP activation. These alterations enhance EMT and the subsequent tumor budding. Tumor budding and ME1 expression are thus considered useful markers of OSCC malignancy, and ME1 is expected to be a relevant target for molecular therapy. |
| first_indexed | 2024-03-10T15:59:42Z |
| format | Article |
| id | doaj.art-595505899f4541e899a16eae24116987 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T15:59:42Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-595505899f4541e899a16eae241169872023-11-20T15:22:16ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-09-012119714910.3390/ijms21197149Malic Enzyme 1 Is Associated with Tumor Budding in Oral Squamous Cell CarcinomasChie Nakashima0Tadaaki Kirita1Kazuhiko Yamamoto2Shiori Mori3Yi Luo4Takamitsu Sasaki5Kiyomu Fujii6Hitoshi Ohmori7Isao Kawahara8Takuya Mori9Kei Goto10Shingo Kishi11Rina Fujiwara-Tani12Hiroki Kuniyasu13Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, JapanDepartment of Oral and Maxillofacial Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, JapanDepartment of Oral and Maxillofacial Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, JapanKey Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, ChinaDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, JapanBudding at the tumor invasive front has been correlated with the malignant properties of many cancers. Malic enzyme 1 (ME1) promotes the Warburg effect in cancer cells and induces epithelial–mesenchymal transition (EMT) in oral squamous cell carcinoma (OSCC). Therefore, we investigated the role of ME1 in tumor budding in OSCC. Tumor budding was measured in 96 human OSCCs by immunostaining for an epithelial marker (AE1/AE3), and its expression was compared with that of ME1. A significant correlation was observed between tumor budding and ME1 expression. The correlation increased with the progression of cancer. In human OSCC cells, lactate secretion decreased when lactate fermentation was suppressed by knockdown of ME1 and lactate dehydrogenase A or inhibition of pyruvate dehydrogenase (PDH) kinase. Furthermore, the extracellular pH increased, and the EMT phenotype was suppressed. In contrast, when oxidative phosphorylation was suppressed by PDH knockdown, lactate secretion increased, extracellular pH decreased, and the EMT phenotype was promoted. Induction of chemical hypoxia in OSCC cells by CoCl<sub>2</sub> treatment resulted in increased ME1 expression along with HIF1α expression and promotion of the EMT phenotype. Hypoxic conditions also increased matrix metalloproteinases expression and decreased mitochondrial membrane potential, mitochondrial oxidative stress, and extracellular pH. Furthermore, the hypoxic treatment resulted in the activation of Yes-associated protein (YAP), which was abolished by ME1 knockdown. These findings suggest that cancer cells at the tumor front in hypoxic environments increase their lactate secretion by switching their energy metabolism from oxidative phosphorylation to glycolysis owing to ME1 overexpression, decrease in extracellular pH, and YAP activation. These alterations enhance EMT and the subsequent tumor budding. Tumor budding and ME1 expression are thus considered useful markers of OSCC malignancy, and ME1 is expected to be a relevant target for molecular therapy.https://www.mdpi.com/1422-0067/21/19/7149ME1tumor buddingEMTextracellular pHhypoxia |
| spellingShingle | Chie Nakashima Tadaaki Kirita Kazuhiko Yamamoto Shiori Mori Yi Luo Takamitsu Sasaki Kiyomu Fujii Hitoshi Ohmori Isao Kawahara Takuya Mori Kei Goto Shingo Kishi Rina Fujiwara-Tani Hiroki Kuniyasu Malic Enzyme 1 Is Associated with Tumor Budding in Oral Squamous Cell Carcinomas International Journal of Molecular Sciences ME1 tumor budding EMT extracellular pH hypoxia |
| title | Malic Enzyme 1 Is Associated with Tumor Budding in Oral Squamous Cell Carcinomas |
| title_full | Malic Enzyme 1 Is Associated with Tumor Budding in Oral Squamous Cell Carcinomas |
| title_fullStr | Malic Enzyme 1 Is Associated with Tumor Budding in Oral Squamous Cell Carcinomas |
| title_full_unstemmed | Malic Enzyme 1 Is Associated with Tumor Budding in Oral Squamous Cell Carcinomas |
| title_short | Malic Enzyme 1 Is Associated with Tumor Budding in Oral Squamous Cell Carcinomas |
| title_sort | malic enzyme 1 is associated with tumor budding in oral squamous cell carcinomas |
| topic | ME1 tumor budding EMT extracellular pH hypoxia |
| url | https://www.mdpi.com/1422-0067/21/19/7149 |
| work_keys_str_mv | AT chienakashima malicenzyme1isassociatedwithtumorbuddinginoralsquamouscellcarcinomas AT tadaakikirita malicenzyme1isassociatedwithtumorbuddinginoralsquamouscellcarcinomas AT kazuhikoyamamoto malicenzyme1isassociatedwithtumorbuddinginoralsquamouscellcarcinomas AT shiorimori malicenzyme1isassociatedwithtumorbuddinginoralsquamouscellcarcinomas AT yiluo malicenzyme1isassociatedwithtumorbuddinginoralsquamouscellcarcinomas AT takamitsusasaki malicenzyme1isassociatedwithtumorbuddinginoralsquamouscellcarcinomas AT kiyomufujii malicenzyme1isassociatedwithtumorbuddinginoralsquamouscellcarcinomas AT hitoshiohmori malicenzyme1isassociatedwithtumorbuddinginoralsquamouscellcarcinomas AT isaokawahara malicenzyme1isassociatedwithtumorbuddinginoralsquamouscellcarcinomas AT takuyamori malicenzyme1isassociatedwithtumorbuddinginoralsquamouscellcarcinomas AT keigoto malicenzyme1isassociatedwithtumorbuddinginoralsquamouscellcarcinomas AT shingokishi malicenzyme1isassociatedwithtumorbuddinginoralsquamouscellcarcinomas AT rinafujiwaratani malicenzyme1isassociatedwithtumorbuddinginoralsquamouscellcarcinomas AT hirokikuniyasu malicenzyme1isassociatedwithtumorbuddinginoralsquamouscellcarcinomas |