Mechanistic Contribution of Ubiquitous 15-Lipoxygenase-1 Expression Loss in Cancer Cells to Terminal Cell Differentiation Evasion

Abstract

Loss of terminal cell differentiation promotes tumorigenesis. 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 in 79% 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 non-transformed bronchial epithelial but not lung cancer cell lines. 15-LOX-1 expression levels were lower in human tumors than 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 re-expression to inhibit tumorigenesis.

Filtrating colorectal cancer associated genes by integrated analyses of global DNA methylation and hydroxymethylation in cancer and normal tissue

“…Some researches have proved down-regulation of ALOX15 in various human cancers (e.g., cancers of the colon252627, breast28, lung29, and pancreas30, supporting the theory that ALOX15 is a tumor suppressor gene in these cancers. Zou et al found that the ALOX15 promoter was methylated in colorectal cancer cells in vitro and in 36% (18/50) of colorectal cancer patients but virtually absent in the normal colons without history of colorectal cancer or polyps31.…”

ALOX15 as a suppressor of inflammation and cancer: Lost in the link

“…In contrast, other LOXs do not appear to be significantly altered during colonic tumorigenesis [31, 73, 74]. Downregulation of ALOX15 expression has also been reported in various other human cancers, including lung [75], esophageal [76], breast [77], endometrial [78], urinary bladder [79] and pancreatic cancer [80]. Additionally, screening of 128 different human cancer cell lines representing 20 different human cancers, including all common human cancers, showed that ALOX15 expression was markedly repressed [75].…”

“…Downregulation of ALOX15 expression has also been reported in various other human cancers, including lung [75], esophageal [76], breast [77], endometrial [78], urinary bladder [79] and pancreatic cancer [80]. Additionally, screening of 128 different human cancer cell lines representing 20 different human cancers, including all common human cancers, showed that ALOX15 expression was markedly repressed [75]. Loss of ALOX15 expression is transcriptionally mediated [81] and independent of substrate availability [31].…”

The role of 15-LOX-1 in colitis and colitis-associated colorectal cancer

“…Recent research shows that loss of 15-LOX-1 expression is ubiquitous in a very large collection of cancer cell lines (128 cell lines from more than 20 types of human cancer, including all of the more common types-lung, breast, colorectal, prostate, esophageal, gastric, pancreas, liver, head and neck, cervical, ovarian, and endometrial) and 15-LOX-1 downregulation in tumors [12]. When the 15-LOX-1 transgene was re-expressed in colonic epithelial cells of two independent mice, azoxymethane-inducible colonic tumorigenesis was suppressed.…”

“…Loss of terminal cell differentiation facilitates tumorigenesis by disrupting the tight cell junction formation required for epithelial-mesenchymal conversion [12]. Studies of reticulocyte maturation into red cells have shown that 15-LOX-1 promotes maturational degradation of organelles [13,14].…”