Abstract
Enhanced migration potential is a common characteristic of cancer cells induced by mechanisms that are incompletely defined. The present study was designed to investigate relationship of a new discovered cytoskeleton regulator MICAL‐L2 and the endogenous epidermal growth factor receptor (EGFR) signalling pathways in gastric cancer cell migration. Increased expression of MICAL‐L2 in gastric cancer cells up‐regulated EGFR protein level, accompanied by the increase of cell migration, whereas silencing MICAL‐L2 down‐regulated EGFR and inhibited cell migration. Expression of MICAL‐L2 was also shown positively correlated with the activation of HSP27/cytoskeleton and HSP27/β‐catenin signalling pathways that provide key mechanisms controlling cell migration. The up‐regulating effect of MICAL‐L2 on EGFR is mediated through a transcription‐independent mechanism that involves inhibiting EGFR protein degradation in lysosome. Further analysis indicated that Cdc42 activation contributed in maintaining the effect of MICAL‐L2 on EGFR stability. Furthermore analysis of clinic specimens revealed increased expression of MICAL‐L2 in carcinoma tissues and a positive correlation between MICAL‐L2 and EGFR expression levels. The above results indicate that MICAL‐L2 potentiates gastric cell migration via inhibiting EGFR degradation in lysosome via a Cdc42‐dependent manner that leads to the activation of EGFR/HSP27 signalling pathways.
Highlights
Gastric cancer is the fifth most common cancer worldwide with 952 000 cases diagnosed in 2012.1 One of the major reasons for its relatively poor prognosis is that cancer cells spread to other parts of the body without showing any symptoms
We demonstrated here that MICAL‐L2 plays an important role in gastric cancer cell migration
We further extended our observation on MICAL‐L2 that lacks flavoprotein monooxygenase (MO) domain and owns C‐terminal domains (CTD) compared with MICAL2.25 We showed that gastric cancer cell migrative potential was greatly impaired, which was likely mediated by the knockdown of MICAL‐L2 expression, whereas over‐ expression of MICAL‐L2 increased cell motility
Summary
Gastric cancer is the fifth most common cancer worldwide with 952 000 cases diagnosed in 2012.1 One of the major reasons for its relatively poor prognosis is that cancer cells spread to other parts of the body without showing any symptoms. Traditional therapies such as chemotherapy and radiotherapy are being used in clinical practice since a long time. Our findings uncover the contexts in which a recognized cytoskeletal protein MICAL‐L2 functions to keep EGFR content and selective inhibition of MICAL‐ L2 may represent a new potential target for gastric cancer metasta‐ sis therapy
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