PD-L1 upregulation is associated with activation of the DNA double-strand break repair pathway in patients with colitic cancer

被引：11

作者：

Ozawa, Naoya ^{[1
]}

Yokobori, Takehiko ^{[2
]}

Osone, Katsuya ^{[1
]}

Katayama, Chika ^{[1
]}

Suga, Kunihiko ^{[1
]}

Komine, Chika ^{[1
]}

Shibasaki, Yuta ^{[1
]}

Shiraishi, Takuya ^{[1
]}

Okada, Takuhisa ^{[1
]}

Kato, Ryuji ^{[1
]}

Ogawa, Hiroomi ^{[1
]}

Sano, Akihiko ^{[1
]}

Sakai, Makoto ^{[1
]}

Sohda, Makoto ^{[1
]}

Ojima, Hitoshi ^{[3
]}

Miyazaki, Tatsuya ^{[4
]}

Motegi, Yoko ^{[4
]}

Ide, Munenori ^{[5
]}

Yao, Takashi ^{[6
]}

Kuwano, Hiroyuki ^{[1
]}

Shirabe, Ken ^{[1
]}

Saeki, Hiroshi ^{[1
]}

机构：

[1] Gunma Univ, Grad Sch Med, Dept Gen Surg Sci, Maebashi, Gumma, Japan

[2] Gunma Univ Initiat Adv Res GIAR, Div Integrated Oncol Res, 3-39-22 Showa Machi, Maebashi, Gumma 3718511, Japan

[3] Gunma Prefectural Canc Ctr, Dept Gastroenterol Surg, Ohta, Gumma, Japan

[4] Maebashi Red Cross Hosp, Dept Gastroenterol Surg, Maebashi, Gumma, Japan

[5] Maebashi Red Cross Hosp, Dept Pathol Diag, Maebashi, Gumma, Japan

[6] Juntendo Univ, Grad Sch Med, Dept Human Pathol, Bunkyo City, Tokyo, Japan

来源：

SCIENTIFIC REPORTS | 2021年 / 11卷 / 01期

关键词：

TUMOR MUTATIONAL BURDEN; ULCERATIVE-COLITIS; ADVANCED MELANOMA; DAMAGE RESPONSE; THERAPY; INFLAMMATION; PROGRESSION; EXPRESSION; NEOPLASIA; DISEASE;

D O I：

10.1038/s41598-021-92530-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Ulcerative colitis (UC) is a DNA damage-associated chronic inflammatory disease; the DNA double-strand break (DSB) repair pathway participates in UC-associated dysplasia/colitic cancer carcinogenesis. The DSB/interferon regulatory factor-1 (IRF-1) pathway can induce PD-L1 expression transcriptionally. However, the association of PD-L1/DSB/IRF-1 with sporadic colorectal cancer (SCRC), and UC-associated dysplasia/colitic cancer, remains elusive. Therefore, we investigated the significance of the PD-L1/DSB repair pathway using samples from 17 SCRC and 12 UC patients with rare UC-associated dysplasia/colitic cancer cases by immunohistochemical analysis. We compared PD-L1 expression between patients with SCRC and UC-associated dysplasia/colitic cancer and determined the association between PD-L1 and the CD8+T-cell/DSB/IRF-1 axis in UC-associated dysplasia/colitic cancer. PD-L1 expression in UC and UC-associated dysplasia/colitic cancer was higher than in normal mucosa or SCRC, and in CD8-positive T lymphocytes in UC-associated dysplasia/colitic cancer than in SCRC. Moreover, PD-L1 upregulation was associated with gamma H2AX (DSB marker) and IRF-1 upregulation in UC-associated dysplasia/colitic cancer. IRF-1 upregulation was associated with gamma H2AX upregulation in UC-associated dysplasia/colitic cancer but not in SCRC. Multicolour immunofluorescence staining validated gamma H2AX/IRF-1/PD-L1 co-expression in colitic cancer tissue sections. Thus, immune cell-induced inflammation might activate the DSB/IRF-1 axis, potentially serving as the primary regulatory mechanism of PD-L1 expression in UC-associated carcinogenesis.

引用

页数：10

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