MUC1 oncoprotein promotes refractoriness to chemotherapy in thyroid cancer cells.
Overexpression of MUC1 oncoprotein is frequently observed in cancer and contributes to confer resistance to genotoxic agents. Papillary, follicular, and anaplastic thyroid carcinomas are the three forms of thyroid epithelial cancer. Anaplastic tumors are less differentiated and extremely aggressive, characterized by a poor prognosis. Little is known about the role of MUC1 in thyroid cancer. We recently showed that autocrine production of interleukin (IL)-4 and IL-10 controls thyroid cancer cell survival, growth, and resistance to chemotherapy through activation of Janus-activated kinase/signal transducers and activators of transcription (JAK/STAT) and phosphatidylinositide 3'-OH kinase (PI3K)/Akt pathways. In the present study, we showed that MUC1 COOH-terminal subunit (MUC1-C) is overexpressed in all the histologic variants of thyroid cancer cells and localizes to mitochondria where it interferes with the release of mitochondrial proapoptotic proteins. Moreover, IL-4 and IL-10 promote the increase of MUC1-C expression levels in normal thyroid cells, whereas blockage of both cytokines or neutralization of JAK/STAT and PI3K/Akt pathways through the exogenous expression of SOCS-1 and Akt(K179M) leads to a significant decrease of MUC1-C in primary thyroid cancer cells. Interestingly, down-regulation of MUC1 expression by direct targeting with RNA interference sensitizes anaplastic thyroid cancer cells to chemotherapy-induced apoptosis in vitro. Thus, MUC1 is a main component of the survival network acting in thyroid cancer and could be considered a key molecular target for sensitizing cancer cells to conventional or novel treatments.
Siragusa
Mauro
M
Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
Zerilli
Monica
M
Iovino
Flora
F
Francipane
Maria Giovanna
MG
Lombardo
Ylenia
Y
Ricci-Vitiani
Lucia
L
Di Gesù
Giuseppe
G
Todaro
Matilde
M
De Maria
Ruggero
R
Stassi
Giorgio
G
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D018396:Mucin-1; D009077:Mucins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; C060192:MUC1 protein, human; D018396:Mucin-1; D009077:Mucins; D034741:RNA, Small Interfering; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016753:Interleukin-10; D015847:Interleukin-4; D004317:Doxorubicin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt