Musashi-1 promotes stress-induced tumor progression through recruitment of AGO2
Authors: Shih-Hwa Chiou
Benoit Laurent
Ming-Teh Chen
Jennifer Hsu
Chung-Pin Li
Wen-Chang Lin
Hsiao-Yun Chen
Chung-Hsuan Chen
Yi-Wei Chen
Mong-Lien Wang
Yi-Ping Yang
Liang-Ting Lin
Pin-I Huang
Chih-Hung Hsu
Wei-Chao Chang
Jia Shen
Hsin-I Ma
Mien-Chie Hung
Journal: Theranostics (2020)
Discipline: CLINICAL MEDICINE
Keywords: Argonaute 2; Musashi-1; RNA regulation; cancer; subcellular translocation
Affiliations: Division of Basic Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan., Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan., Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan., Institute of Food Safety and Health Risk Assessment, School of Pharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan., Boston Children Hospital and Harvard Medical School, Boston MA, USA., Department of Public Health, and Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China., Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston, and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA., Department of Neurosurgery, Taipei Veterans General Hospital, Taipei, Taiwan., Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan., Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan., Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan., Genomic Research Center, Academia Sinica, Taipei, Taiwan., Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

Abstract:  Carcinomatous progression and recurrence are the main therapeutic challenges frequently faced by patients with refractory tumors. However, the underlined molecular mechanism remains obscure. Methods: We found Musashi-1 (MSI1) transported into cytosol under stress condition by confocal microscopy and cell fractionation. Argonaute 2 (AGO2) was then identified as a cytosolic binding partner of MSI1 by Mass Spectrametry, immunoprecipitation, and recombinant protein pull-down assay. We used RNA-IP to determine the MSI1/AGO2 associated regions on downstream target mRNAs. Finally, we overexpressed C-terminus of MSI1 to disrupt endogenous MSI1/AGO2 interaction and confirm it effects on tmor progression. Results: Malignant tumors exhibit elevated level of cytosolic Musashi-1 (MSI1), which translocates into cytosol in response to stress and promote tumor progression. Cytosolic MSI1 forms a complex with AGO2 and stabilize or destabilize its target mRNAs by respectively binding to their 3¬¥ untranslated region or coding domain sequence. Both MSI1 translocation and MSI1/AGO2 binding are essential for promoting tumor progression. Blocking MSI1 shuttling by either chemical inhibition or point mutation attenuates the growth of GBM-xenografts in mice. Importantly, overexpression of the C-terminus of MSI1 disrupts endogenous MSI1/AGO2 interaction and effectively reduces stress-induced tumor progression. Conclusion: Our findings highlight novel molecular functions of MSI1 during stress-induced carcinomatous recurrence, and suggest a new therapeutic strategy for refractory malignancies by targeting MSI1 translocation and its interaction with AGOs. 

Retracted: No

PubPeer comments:
 Fig 4C appears to have 3 sets of images which overlap (roughly indicated in cyan, green, and yellow), although they may not be identical. ***  *** Full figure  , 
 Figure 7F appears to include a repeated DAPI panel. *** Contrast enhanced  , 
 This is Hsiao-Yun and Ming-Lien, the ranked-first and co-first author of the paper. We want to thank the peers for their interest. We apologize to our readers for the unintentional misplaced IF images and already found the correct images from our raw data, which will be submitted to the journal soon. These changes do not affect any interpretations or conclusions of this work. Thanks for the keen eyes of peers. , 
 1A and 8A appear to have an overlap. I am uncertain whether this is intended. ***  , 
 We have checked our data and discussed it with Hsiao-Yun and co-authors. For the presentation of the data, the IHC image in Figure 1A (top right panel) is a representative case of primary GBM tumors. Figure 1A just shows the cytoplasmic localization of MSI1 in primary GBM tissue, presenting a different pattern from recurrent GBM in the lower panel. The top-right panel is also described as a primary GBM tumor in our result and the legend. In Figure 8A, we further use paired tissue samples to show the difference between primary GBM (from the 1st operation GBM tissue) and recurrent GBM (from the 2nd operation GBM tissue) samples. The tissues in Figure 8A are also primary GBM tumors. The presented images consistent with our description and figure legends. ,