MUC1 is a downstream target of STAT3 and regulates lung cancer cell survival and invasion.
Signal transducer and activator of transcription 3 (STAT3) is aberrantly activated in human cancer including lung cancer and has been implicated in transformation, tumorigenicity, and metastasis. One putative downstream gene regulated by Stat3 is MUC1 which also has important roles in tumorigenesis. We determined if Stat3 regulates MUC1 in lung cancer cell lines and what function MUC1 plays in lung cancer cell biology. We examined MUC1 expression in non-small cell lung cancer (NSCLC) cell lines and found high levels of MUC1 protein expression associated with higher levels of tyrosine phosphorylated STAT3. STAT3 knockdown downregulated MUC1 expression whereas constitutive STAT3 expression increased MUC1 expression at mRNA and protein levels. MUC1 knockdown induced cellular apoptosis concomitant with reduced Bcl-XL and sensitized cells to cisplatin treatment. MUC1 knockdown inhibited tumor growth and metastasis in an orthotopic mouse model of lung cancer by activating apoptosis and inhibiting cell proliferation in vivo. These results demonstrate that constitutively activated STAT3 regulates expression of MUC1, which mediates lung cancer cell survival and metastasis in vitro and in vivo. MUC1 appears to be a cooperating oncoprotein with multiple oncogenic tyrosine kinase pathways and could be an effective target for the treatment of lung cancer.
Gao
Jingchun
J
Department of Thoracic Oncology and Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
McConnell
Matthew J
MJ
Yu
Bin
B
Li
Jiannong
J
Balko
Justin M
JM
Black
Esther P
EP
Johnson
Joseph O
JO
Lloyd
Mark C
MC
Altiok
Soner
S
Haura
Eric B
EB
D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000627:therapeutic use; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D018396:Mucin-1 / Q000235:genetics / Q000502:physiology*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction
C060192:MUC1 protein, human; D018396:Mucin-1; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin