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The Role of Bip and the Ire1α–Xbp1 Axis in Rhabdomyosarcoma Pathology Publisher



Aghaei M1, 2 ; Nasimian A2, 3 ; Rahmati M4 ; Kawalec P2 ; Machaj F2 ; Rosik J2 ; Bhushan B2 ; Bathaie SZ3, 5 ; Azarpira N6 ; Los MJ7 ; Samali A8 ; Perrin D9 ; Gordon JW10 ; Ghavami S2, 11, 12, 13, 14
Authors
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Authors Affiliations
  1. 1. Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran
  2. 2. Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, R3E 0V9, MB, Canada
  3. 3. Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, 14155-331, Iran
  4. 4. Cancer Biology Research Center, Tehran University of Medical Sciences, Tehran, 14197-33141, Iran
  5. 5. Institute for Natural Products and Medicinal Plants, Tarbiat Modares University, Tehran, 14155-331, Iran
  6. 6. Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, 7134814336, Iran
  7. 7. Biotechnology Center, Silesian University of Technology, Gliwice, 71-344, Poland
  8. 8. Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, Galway, H91 W2TY, Ireland
  9. 9. Section of Orthopaedic Surgery, Department of Surgery, University of Manitoba, Winnipeg, R3E 0V9, MB, Canada
  10. 10. College of Nursing, Rady Faculty of Health Science, University of Manitoba, Winnipeg, R3E 0V9, MB, Canada
  11. 11. Research Institutes of Oncology and Hematology, Cancer Care Manitoba-University of Manitoba, Winnipeg, R3E 0V9, MB, Canada
  12. 12. Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, R3E 0V9, MB, Canada
  13. 13. Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, 7134845794, Iran
  14. 14. Faculty of Medicine, Katowice School of Technology, Katowice, 40-555, Poland

Source: Cancers Published:2021


Abstract

Background: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, and is associated with a poor prognosis in patients presenting with recurrent or metastatic disease. The unfolded protein response (UPR) plays pivotal roles in tumor development and resistance to therapy, including RMS. Methods: In this study, we used immunohistochemistry and a tissue microarray (TMA) on human RMS and normal skeletal muscle to evaluate the expression of key UPR proteins (GRP78/BiP, IRE1α and cytosolic/nuclear XBP1 (spliced XBP1-sXBP1)) in the four main RMS subtypes: alveolar (ARMS), embryonal (ERMS), pleomorphic (PRMS) and sclerosing/spindle cell (SRMS) RMS. We also investigated the correlation of these proteins with the risk of RMS and several clinicopathological indices, such as lymph node involvement, distant metastasis, tumor stage and tumor scores. Results: Our results revealed that the expression of BiP, sXBP1, and IRE1α, but not cytosolic XBP1, are significantly associated with RMS (BiP and sXBP1 p-value = 0.0001, IRE1 p-value = 0.001) in all of the studied types of RMS tumors (n = 192) compared to normal skeletal muscle tissues (n = 16). In addition, significant correlations of BiP with the lymph node score (p = 0.05), and of IRE1α (p value = 0.004), cytosolic XBP1 (p = 0.001) and sXBP1 (p value = 0.001) with the stage score were observed. At the subtype level, BiP and sXBP1 expression were significantly associated with all subtypes of RMS, whereas IRE1α was associated with ARMS, PRMS and ERMS, and cytosolic XBP1 expression was associated with ARMS and SRMS. Importantly, the expression levels of IRE1α and sXBP1 were more pronounced in ARMS than in any of the other subtypes. The results also showed correlations of BiP with the lymph node score in ARMS (p value = 0.05), and of sXBP1 with the tumor score in PRMS (p value = 0.002). Conclusions: In summary, this study demonstrates that the overall UPR is upregulated and, more specifically, that the IRE1/sXBP1 axis is active in RMS. The subtype and stage-specific dependency on the UPR machinery in RMS may open new avenues for the development of novel targeted therapeutic strategies and the identification of specific tumor markers in this rare but deadly childhood and young-adult disease.. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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