Human papillomavirus type 16/18 up-regulates the expression of interleukin-6 and antiapoptotic Mcl-1 in non-small cell lung cancer.
OBJECTIVE
Human papillomavirus (HPV) 16/18 infection is reported to be associated with nonsmoking Taiwanese female lung cancer. In this study, we attempted to further reveal the association between HPV infection with Mcl-1 and interleukin (IL)-6 expressions and to elucidate the roles of HPV infection in lung tumorigenesis.


METHODS
IL-6 and Mcl-1 expressions were investigated in 79 tumor tissues from lung cancer patients by immunohistochemistry. Secreting IL-6 levels and Mcl-1 expressions were examined by ELISA and Western blot, respectively, in HPV 16/18 E6- and E7-transfected A549 human lung cancer cells, as well as in the HPV16-infected TL-1 lung cancer cells established from lung cancer patients.


RESULTS
Lung tumors (70.9% and 57.0%) had positive IL-6 and Mcl-1 immunostainings, respectively. Significant correlation between IL-6 and Mcl-1 expression were observed (P < 0.0001). Both IL-6 and Mcl-1 expression were significantly associated with HPV 16/18 infection (P = 0.014 and P = 0.004, respectively). IL-6 and Mcl-1 protein levels were not only elevated in HPV 16/18 E6- and E7-transfected A549 cells but also in TL-1 cells. Phosphatidylinositol-3-OH kinase pathway was the major pathway contributing to the up-regulation of Mcl-1 by IL-6 in HPV-infected lung cancer cells.


CONCLUSIONS
The up-regulating effects of HPV 16/18 E6 and E7 to IL-6 and Mcl-1 expressions were observed in E6- and E7-transfected A549 cells and in HPV16-infected TL-1 cells, mainly through the phosphatidylinositol-3-OH kinase pathway. The involvement of HPV infection in lung tumorigenesis may be partly through a concomitant increased expression of autocrine and/or paracrine IL-6 and the downstream Mcl-1.
Cheng
Ya-Wen
YW
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Lee
Huei
H
Shiau
Ming-Yuh
MY
Wu
Tzu-Chin
TC
Huang
Tsung-Teng
TT
Chang
Yih-Hsin
YH
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D052162:Human papillomavirus 16 / Q000378:metabolism*; D052161:Human papillomavirus 18 / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*
D015850:Interleukin-6; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2