<i>miR-31</i>-<i>NUMB</i> Cascade Modulates Monocarboxylate Transporters to Increase Oncogenicity and Lactate Production of Oral Carcinoma Cells

<i>miR-31</i>-<i>NUMB</i> Cascade Modulates Monocarboxylate Transporters to Increase Oncogenicity and Lactate Production of Oral Carcinoma Cells

Oral squamous cell carcinoma (OSCC) is among the leading causes of cancer-associated death worldwide. <i>miR-31</i> is an oncogenic miRNA in OSCC. NUMB is an adaptor protein capable of suppressing malignant transformation. Disruption of the <i>miR-31</i>-<i>NUMB</i&g...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Chung-Hsien Chou, Chun-Yu Fan Chiang, Cheng-Chieh Yang, Ying-Chieh Liu, Sih-Rou Chang, Kuo-Wei Chang, Shu-Chun Lin
Formato: article
Lenguaje:EN
Publicado: MDPI AG 2021
Materias:
CRISPR
lactate
<i>MCT1</i>
<i>MCT4</i>
<i>miR-31</i>
<i>NUMB</i>
Biology (General)
QH301-705.5
Chemistry
QD1-999
Acceso en línea:https://doaj.org/article/d858cb94452b47c89ce80db39bb95cb9
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:d858cb94452b47c89ce80db39bb95cb9
record_format dspace
spelling oai:doaj.org-article:d858cb94452b47c89ce80db39bb95cb92021-11-11T17:11:12Z<i>miR-31</i>-<i>NUMB</i> Cascade Modulates Monocarboxylate Transporters to Increase Oncogenicity and Lactate Production of Oral Carcinoma Cells10.3390/ijms2221117311422-00671661-6596https://doaj.org/article/d858cb94452b47c89ce80db39bb95cb92021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11731https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Oral squamous cell carcinoma (OSCC) is among the leading causes of cancer-associated death worldwide. <i>miR-31</i> is an oncogenic miRNA in OSCC. NUMB is an adaptor protein capable of suppressing malignant transformation. Disruption of the <i>miR-31</i>-<i>NUMB</i> regulatory axis has been demonstrated in malignancies. Mitochondrial dysfunction and adaptation to glycolytic respiration are frequent events in malignancies. Monocarboxylate transporters (MCTs) function to facilitate lactate flux in highly glycolytic cells. Upregulation of <i>MCT1</i> and <i>MCT4</i> has been shown to be a prognostic factor of OSCC. Here, we reported that <i>miR-31-NUMB</i> can modulate glycolysis in OSCC. Using the CRISPR/Cas9 gene editing strategy, we identified increases in oncogenic phenotypes, <i>MCT1</i> and <i>MCT4</i> expression, lactate production, and glycolytic respiration in <i>NUMB</i>-deleted OSCC subclones. Transfection of the <i>Numb1</i> or <i>Numb4</i> isoform reversed the oncogenic induction elicited by <i>NUMB</i> deletion. This study also showed, for the first time, that NUMB4 binds MCT1 and MCT4 and that this binding increases their ubiquitination, which may decrease their abundance in cell lysates. The disruptions in oncogenicity and metabolism associated with <i>miR-31</i> deletion and <i>NUMB</i> deletion were partially rescued by <i>MCT1</i>/<i>MCT4</i> expression or knockdown. This study demonstrated that NUMB is a novel binding partner of MCT1 and MCT4 and that the <i>miR-31</i>-<i>NUMB</i>-<i>MCT1/MCT4</i> regulatory cascade is present in oral carcinoma.Chung-Hsien ChouChun-Yu Fan ChiangCheng-Chieh YangYing-Chieh LiuSih-Rou ChangKuo-Wei ChangShu-Chun LinMDPI AGarticleCRISPRlactate<i>MCT1</i><i>MCT4</i><i>miR-31</i><i>NUMB</i>Biology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11731, p 11731 (2021)
institution DOAJ
collection DOAJ
language EN
topic CRISPR
lactate
<i>MCT1</i>
<i>MCT4</i>
<i>miR-31</i>
<i>NUMB</i>
Biology (General)
QH301-705.5
Chemistry
QD1-999
spellingShingle CRISPR
lactate
<i>MCT1</i>
<i>MCT4</i>
<i>miR-31</i>
<i>NUMB</i>
Biology (General)
QH301-705.5
Chemistry
QD1-999
Chung-Hsien Chou
Chun-Yu Fan Chiang
Cheng-Chieh Yang
Ying-Chieh Liu
Sih-Rou Chang
Kuo-Wei Chang
Shu-Chun Lin
<i>miR-31</i>-<i>NUMB</i> Cascade Modulates Monocarboxylate Transporters to Increase Oncogenicity and Lactate Production of Oral Carcinoma Cells
description Oral squamous cell carcinoma (OSCC) is among the leading causes of cancer-associated death worldwide. <i>miR-31</i> is an oncogenic miRNA in OSCC. NUMB is an adaptor protein capable of suppressing malignant transformation. Disruption of the <i>miR-31</i>-<i>NUMB</i> regulatory axis has been demonstrated in malignancies. Mitochondrial dysfunction and adaptation to glycolytic respiration are frequent events in malignancies. Monocarboxylate transporters (MCTs) function to facilitate lactate flux in highly glycolytic cells. Upregulation of <i>MCT1</i> and <i>MCT4</i> has been shown to be a prognostic factor of OSCC. Here, we reported that <i>miR-31-NUMB</i> can modulate glycolysis in OSCC. Using the CRISPR/Cas9 gene editing strategy, we identified increases in oncogenic phenotypes, <i>MCT1</i> and <i>MCT4</i> expression, lactate production, and glycolytic respiration in <i>NUMB</i>-deleted OSCC subclones. Transfection of the <i>Numb1</i> or <i>Numb4</i> isoform reversed the oncogenic induction elicited by <i>NUMB</i> deletion. This study also showed, for the first time, that NUMB4 binds MCT1 and MCT4 and that this binding increases their ubiquitination, which may decrease their abundance in cell lysates. The disruptions in oncogenicity and metabolism associated with <i>miR-31</i> deletion and <i>NUMB</i> deletion were partially rescued by <i>MCT1</i>/<i>MCT4</i> expression or knockdown. This study demonstrated that NUMB is a novel binding partner of MCT1 and MCT4 and that the <i>miR-31</i>-<i>NUMB</i>-<i>MCT1/MCT4</i> regulatory cascade is present in oral carcinoma.
format article
author Chung-Hsien Chou
Chun-Yu Fan Chiang
Cheng-Chieh Yang
Ying-Chieh Liu
Sih-Rou Chang
Kuo-Wei Chang
Shu-Chun Lin
author_facet Chung-Hsien Chou
Chun-Yu Fan Chiang
Cheng-Chieh Yang
Ying-Chieh Liu
Sih-Rou Chang
Kuo-Wei Chang
Shu-Chun Lin
author_sort Chung-Hsien Chou
title <i>miR-31</i>-<i>NUMB</i> Cascade Modulates Monocarboxylate Transporters to Increase Oncogenicity and Lactate Production of Oral Carcinoma Cells
title_short <i>miR-31</i>-<i>NUMB</i> Cascade Modulates Monocarboxylate Transporters to Increase Oncogenicity and Lactate Production of Oral Carcinoma Cells
title_full <i>miR-31</i>-<i>NUMB</i> Cascade Modulates Monocarboxylate Transporters to Increase Oncogenicity and Lactate Production of Oral Carcinoma Cells
title_fullStr <i>miR-31</i>-<i>NUMB</i> Cascade Modulates Monocarboxylate Transporters to Increase Oncogenicity and Lactate Production of Oral Carcinoma Cells
title_full_unstemmed <i>miR-31</i>-<i>NUMB</i> Cascade Modulates Monocarboxylate Transporters to Increase Oncogenicity and Lactate Production of Oral Carcinoma Cells
title_sort <i>mir-31</i>-<i>numb</i> cascade modulates monocarboxylate transporters to increase oncogenicity and lactate production of oral carcinoma cells
publisher MDPI AG
publishDate 2021
url https://doaj.org/article/d858cb94452b47c89ce80db39bb95cb9
work_keys_str_mv AT chunghsienchou imir31iinumbicascademodulatesmonocarboxylatetransporterstoincreaseoncogenicityandlactateproductionoforalcarcinomacells
AT chunyufanchiang imir31iinumbicascademodulatesmonocarboxylatetransporterstoincreaseoncogenicityandlactateproductionoforalcarcinomacells
AT chengchiehyang imir31iinumbicascademodulatesmonocarboxylatetransporterstoincreaseoncogenicityandlactateproductionoforalcarcinomacells
AT yingchiehliu imir31iinumbicascademodulatesmonocarboxylatetransporterstoincreaseoncogenicityandlactateproductionoforalcarcinomacells
AT sihrouchang imir31iinumbicascademodulatesmonocarboxylatetransporterstoincreaseoncogenicityandlactateproductionoforalcarcinomacells
AT kuoweichang imir31iinumbicascademodulatesmonocarboxylatetransporterstoincreaseoncogenicityandlactateproductionoforalcarcinomacells
AT shuchunlin imir31iinumbicascademodulatesmonocarboxylatetransporterstoincreaseoncogenicityandlactateproductionoforalcarcinomacells
_version_ 1718432148071907328

Ejemplares similares