Autophagy regulates cisplatin-induced stemness and chemoresistance via the upregulation of CD44, ABCB1 and ADAM17 in oral squamous cell carcinoma

作者：Naik Prajna Paramita; Mukhopadhyay Subhadip; Panda Prashanta Kumar; Sinha Niharika; Das Chandan Kanta; Mishra Rajakishore; Patil Shankargouda; Bhutia Sujit Kumar

来源：Cell Proliferation, 2018, 51(1): e12411.

DOI：10.1111/cpr.12411

<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>We inspected the relevance of <jats:styled-content style="fixed-case">CD</jats:styled-content>44, <jats:styled-content style="fixed-case">ABCB</jats:styled-content>1 and <jats:styled-content style="fixed-case">ADAM</jats:styled-content>17 in <jats:styled-content style="fixed-case">OSCC</jats:styled-content> stemness and deciphered the role of autophagy/mitophagy in regulating stemness and chemoresistance.</jats:p></jats:sec><jats:sec><jats:title>Material and methods</jats:title><jats:p>A retrospective analysis of <jats:styled-content style="fixed-case">CD</jats:styled-content>44, <jats:styled-content style="fixed-case">ABCB</jats:styled-content>1 and <jats:styled-content style="fixed-case">ADAM</jats:styled-content>17 with respect to the various clinico‐pathological factors and their correlation was analysed in sixty <jats:styled-content style="fixed-case">OSCC</jats:styled-content> samples. Furthermore, the stemness and chemoresistance were studied in resistant oral cancer cells using sphere formation assay, flow cytometry and florescence microscopy. The role of autophagy/mitophagy was investigated by transient transfection of si<jats:styled-content style="fixed-case">ATG</jats:styled-content>14, <jats:styled-content style="fixed-case">GFP</jats:styled-content>‐<jats:styled-content style="fixed-case">LC</jats:styled-content>3, <jats:styled-content style="fixed-case">tF</jats:styled-content>‐<jats:styled-content style="fixed-case">LC</jats:styled-content>3, <jats:styled-content style="fixed-case">mK</jats:styled-content>eima‐Red‐Mito7 and Western blot analysis of autophagic and mitochondrial proteins.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In <jats:styled-content style="fixed-case">OSCC</jats:styled-content>, high <jats:styled-content style="fixed-case">CD</jats:styled-content>44, <jats:styled-content style="fixed-case">ABCB</jats:styled-content>1 and <jats:styled-content style="fixed-case">ADAM</jats:styled-content>17 expressions were correlated with higher tumour grades and poor differentiation and show significant correlation in their co‐expression. In vitro and <jats:styled-content style="fixed-case">OSCC</jats:styled-content> tissue double labelling confirmed that <jats:styled-content style="fixed-case">CD</jats:styled-content>44<jats:sup>+</jats:sup> cells co‐expresses <jats:styled-content style="fixed-case">ABCB</jats:styled-content>1 and <jats:styled-content style="fixed-case">ADAM</jats:styled-content>17. Further, cisplatin (<jats:styled-content style="fixed-case">CDDP</jats:styled-content>)‐resistant FaDu cells displayed stem‐like features and higher <jats:styled-content style="fixed-case">CD</jats:styled-content>44, <jats:styled-content style="fixed-case">ABCB</jats:styled-content>1 and <jats:styled-content style="fixed-case">ADAM</jats:styled-content>17 expression. Higher autophagic flux and mitophagy were observed in resistant FaDu cells as compared to parental cells, and inhibition of autophagy led to the decrease in stemness, restoration of mitochondrial proteins and reduced expression of <jats:styled-content style="fixed-case">CD</jats:styled-content>44, <jats:styled-content style="fixed-case">ABCB</jats:styled-content>1 and <jats:styled-content style="fixed-case">ADAM</jats:styled-content>17.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>The <jats:styled-content style="fixed-case">CD</jats:styled-content>44<jats:sup>+</jats:sup>/<jats:styled-content style="fixed-case">ABCB</jats:styled-content>1<jats:sup>+</jats:sup>/<jats:styled-content style="fixed-case">ADAM</jats:styled-content>17<jats:sup>+</jats:sup> expression in <jats:styled-content style="fixed-case">OSCC</jats:styled-content> is associated with stemness and chemoresistance. Further, this study highlights the involvement of mitophagy in chemoresistance and autophagic regulation of stemness in <jats:styled-content style="fixed-case">OSCC</jats:styled-content>.</jats:p></jats:sec>

• 出版日期2018-2