Mechanistic contribution of ubiquitous 15-lipoxygenase-1 expression loss in cancer cells to terminal cell differentiation evasion

Micheline J. Moussalli, Yuanqing Wu, Xiangsheng Zuo, Xiu L. Yang, Ignacio Ivan Wistuba, Maria G. Raso, Jeffrey S. Morris, Jessica L. Bowser, John D. Minna, Reuben Lotan, Imad Shureiqi

Research output: Contribution to journalArticle

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Abstract

Loss of terminal cell differentiation promotes tumorigenesis. 15-Lipoxygenase-1 (15-LOX-1) contributes to terminal cell differentiation in normal cells. The mechanistic significance of 15-LOX-1 expression loss in human cancers to terminal cell differentiation suppression is unknown. In a screen of 128 cancer cell lines representing more than 20 types of human cancer, we found that 15-LOX-1 mRNA expression levels were markedly lower than levels in terminally differentiated cells. Relative expression levels of 15-LOX-1 (relative to the level in terminally differentiated primary normal human-derived bronchial epithelial cells) were lower in79%of the screened cancer cell lines than relative expression levels of p16 (INK4A), which promotes terminal cell differentiation and is considered one of the most commonly lost tumor suppressor genes in cancer cells. 15-LOX-1 was expressed during terminal differentiation in three-dimensional air-liquid interface cultures, and 15-LOX-1 expression and terminal differentiation occurred in immortalized nontransformed bronchial epithelial but not in lung cancer cell lines. 15-LOX-1 expression levels were lower in human tumors than in paired normal lung epithelia. Short hairpin RNA-mediated downregulation of 15- LOX-1 in Caco-2 cells blocked enterocyte-like differentiation, disrupted tight junction formation, and blocked E-cadherin and ZO-1 localization to the cell wall membrane. 15-LOX-1 episomal expression in Caco-2 and HT-29 colon cancer cells induced differentiation. Our findings indicate that 15-LOX-1 downregulation in cancer cells is an important mechanism for terminal cell differentiation dysregulation and support the potential therapeutic utility of 15-LOX-1 reexpression to inhibit tumorigenesis.

Original languageEnglish (US)
Pages (from-to)1961-1972
Number of pages12
JournalCancer Prevention Research
Volume4
Issue number12
DOIs
StatePublished - Dec 2011

Fingerprint

Arachidonate 15-Lipoxygenase
Lipoxygenase
Cell Differentiation
Neoplasms
Cadherins
Cell Line
Carcinogenesis
Down-Regulation
Cyclin-Dependent Kinase Inhibitor p16
Caco-2 Cells
Enterocytes
Tight Junctions
Tumor Suppressor Genes
Colonic Neoplasms
Cell Wall
Small Interfering RNA
Lung Neoplasms
Epithelium
Epithelial Cells
Air

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Mechanistic contribution of ubiquitous 15-lipoxygenase-1 expression loss in cancer cells to terminal cell differentiation evasion. / Moussalli, Micheline J.; Wu, Yuanqing; Zuo, Xiangsheng; Yang, Xiu L.; Wistuba, Ignacio Ivan; Raso, Maria G.; Morris, Jeffrey S.; Bowser, Jessica L.; Minna, John D.; Lotan, Reuben; Shureiqi, Imad.

In: Cancer Prevention Research, Vol. 4, No. 12, 12.2011, p. 1961-1972.

Research output: Contribution to journalArticle

Moussalli, MJ, Wu, Y, Zuo, X, Yang, XL, Wistuba, II, Raso, MG, Morris, JS, Bowser, JL, Minna, JD, Lotan, R & Shureiqi, I 2011, 'Mechanistic contribution of ubiquitous 15-lipoxygenase-1 expression loss in cancer cells to terminal cell differentiation evasion', Cancer Prevention Research, vol. 4, no. 12, pp. 1961-1972. https://doi.org/10.1158/1940-6207.CAPR-10-0280
Moussalli, Micheline J. ; Wu, Yuanqing ; Zuo, Xiangsheng ; Yang, Xiu L. ; Wistuba, Ignacio Ivan ; Raso, Maria G. ; Morris, Jeffrey S. ; Bowser, Jessica L. ; Minna, John D. ; Lotan, Reuben ; Shureiqi, Imad. / Mechanistic contribution of ubiquitous 15-lipoxygenase-1 expression loss in cancer cells to terminal cell differentiation evasion. In: Cancer Prevention Research. 2011 ; Vol. 4, No. 12. pp. 1961-1972.
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