Data from: The role of BiP and the IRE1α-XBP1 axis in rhabdomyosarcoma pathology

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.