Intest Res.  2017 Jan;15(1):75-82. 10.5217/ir.2017.15.1.75.

15-Hydroxyprostaglandin dehydrogenase as a marker in colon carcinogenesis: analysis of the prostaglandin pathway in human colonic tissue

• Yang DH
• Ryu YM
• Lee SM
• Jeong JY
• Yoon SM
• Ye BD
• Byeon JS
• Yang SK
• Myung SJ

• KMID: 2368488
• DOI: http://doi.org/10.5217/ir.2017.15.1.75

Abstract

BACKGROUND/AIMS
Cyclooxygenase-2 (COX-2), 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and microsomal prostaglandin E synthase-1 (mPGEs-1) regulate prostaglandin Eâ‚‚ (PGEâ‚‚) expression and are involved in colon carcinogenesis. We investigated the expression of PGEâ‚‚ and its regulating genes in sporadic human colon tumors and matched normal tissues.
METHODS
Twenty colonic adenomas and 27 colonic adenocarcinomas were evaluated. COX-2 and 15-PGDH expression was quantified by real-time polymerase chain reaction. The expression of PGEâ‚‚ and mPGEs-1 was measured using enzyme-linked immunosorbent assay and Western blotting, respectively.
RESULTS
The expression of COX-2, mPGEs-1, and PGEâ‚‚ did not differ between the adenomas and matched distant normal tissues. 15-PGDH expression was lower in adenomas than in the matched normal colonic tissues (P<0.001). In adenocarcinomas, mPGEs-1 and PGEâ‚‚ expression was significantly higher (P<0.001 and P=0.020, respectively), and COX-2 expression did not differ from that in normal tissues (P=0.207). 15-PGDH expression was significantly lower in the normal colonic mucosa from adenocarcinoma patients than in the normal mucosa from adenoma patients (P=0.018).
CONCLUSIONS
Early inactivation of 15-PGDH, followed by activation of COX-2 and mPGEs-1, contributes to PGEâ‚‚ production, leading to colon carcinogenesis. 15-PGDH might be a novel candidate marker for early detection of field defects in colon carcinogenesis.

Keyword

15-Hydroxyprostaglandin dehydrogenase; Colon; Carcinogenesis

MeSH Terms

Adenocarcinoma
Adenoma
Blotting, Western
Carcinogenesis*
Colon*
Cyclooxygenase 2
Enzyme-Linked Immunosorbent Assay
Humans*
Mucous Membrane
Oxidoreductases*
Real-Time Polymerase Chain Reaction
Cyclooxygenase 2
Oxidoreductases

Figure

• 

  Fig. 1 A representative Western blot for mPGEs-1. After Western blot, expression level of mPGEs-1 was normalized to β-actin and quantified using imaging analyzer to compare normal tissues with adenoma or adenocarcinoma. mPGEs-1, microsomal prostaglandin E synthase-1; N, paired normal tissue of the adenoma or adenocarcinoma; A, adenoma; CA, adenocarcinoma.

• 

  Fig. 2 Comparison between colonic adenoma and matched normal colonic tissue. (A) Expression of COX-2 and 15-PGDH was measured by quantitative real-time PCR; relative expression is presented as log-transformed data. After Western blotting, mPGEs-1 expression normalized to β-actin was further quantified using imaging analyzer; data have been presented as log-transformed values. (B) PGE2 level, as measured by ELISA. Statistical analysis was performed using log-transformed data, but the figure shows the data after back transformation. COX-2, cyclooxygenase-2; 15-PGDH, 15-hydroxyprostaglandin dehydrogenase; mPGEs-1, microsomal prostaglandin E synthase-1; PGE2, prostaglandin E2.

• 

  Fig. 3 Comparison between colonic adenocarcinoma and matched normal colonic tissue. (A) Expression of COX-2 and 15-PGDH was measured using quantitative real-time PCR; relative expression is presented as log-transformed data. After Western blotting, mPGEs-1 expression normalized to β-actin was quantified using imaging analyzer. This is presented as log-transformed data. (B) PGE2 level, as measured by ELISA. Statistical analysis was performed using log-transformed data, but the figure shows the data after back transformation. COX-2, cyclooxygenase-2; 15-PGDH, 15-hydroxy-prostaglandin dehydrogenase; mPGEs-1, microsomal prostaglandin E synthase-1; PGE2, prostaglandin E2.

• 

  Fig. 4 Comparison between colonic adenoma and adenocarcinoma. (A) Expression of COX-2 and 15-PGDH was measured by quantitative real-time PCR; relative expression is presented as log-transformed data. After Western blotting, mPGEs-1 expression normalized to β-actin was quantified using imaging analyzer. This has been presented as log-transformed data. (B) PGE2 level, as measured by ELISA. Statistical analysis was performed using log-transformed data, but the figure shows the data after back transformation. COX-2, cyclooxygenase-2; 15-PGDH, 15-hydroxyprostaglandin dehydrogenase; mPGEs-1, microsomal prostaglandin E synthase-1; PGE2, prostaglandin E2.

• 

  Fig. 5 Comparison of normal colonic tissues from normal subjects (white bar), patients with adenoma (gray bar), and patients with adenocarcinoma (black bar). COX-2 and 15-PGDH expression, as measured by quantitative real-time PCR. The data are presented after back transformation. COX-2, cyclooxygenase-2; 15-PGDH, 15-hydroxyprostaglandin dehydrogenase.

• 

  Fig. 6 15-PGDH immunohistochemistry in the colonic adenoma and adenocarcinoma. (A) Colonic tubular adenoma. The adenomatous tissue stained weakly for 15-PGDH immunohistochemistry. The adjacent normal tissue on the left side of the adenoma was highly positive for 15-PGDH. (B) Colonic adenocarcinoma. The carcinomatous tissue remains unstained. On the contrary, the adjacent normal tissue stained strongly. (C) Graphical representation of 15-PGDH immunohistochemical staining scores for both colonic adenomas and adenocarcinomas. 15-PGDH, 15-hydroxyprostaglandin dehydrogenase.

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