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Circulating microRNA/isomiRs as novel biomarkers of esophageal squamous cell carcinoma

伊富貴 雄太 広島大学

2020.08.27

概要

本研究では、血液中に存在するマイクロRNA(miR)とその類似体であるisomiRが食道扁平上皮癌の新規バイオマーカーとなり得るかを検討した。

マイクロRNAはタンパク質をコードしない、19-25塩基対からなるsmallRNAの一つで、メッセンジャーRNAに作用することで遺伝子発現を制御している。腫瘍細胞由来のmiRは血液中にエクソソームに内包された形で運搬され、腫瘍の進展、転移に有利な状態を作り出すと考えられている。癌患者と健常者ではmiRの発現プロファイルが異なることから診断バイオマーカーとしての有用性が多く報告されている。近年次世代シークエンサー（NGS）研究の発展によりマイクロRNAと近似した塩基配列をもつisomiRの存在が明らかにされた。血液中にも豊富に存在するisomiRは各癌腫の新規バイオマーカーとして注目されているが、実際の報告はまだほとんどない。今回我々はNGS解析により同定された血中miRとisomiRが食道扁平上皮癌（ESCC）の新規バイオマーカーとなり得るかを検討した。

研究の概要としてはESCC患者から採取した血清検体と年齢、性別をマッチさせた健常者（HC）検体からsmallRNAを抽出し、その発現の差異を評価した。異なる集団でバイオマーカーの定義を満たす複数のmiR/isomiRを組み合わせた診断パネルを作成した。

最初の検討ではESCC18例とHC12例を比較した（第1群）。次に異なるESCC30例とHC30例で第1群での候補が再現性をもってバイオマーカーの定義を満たすかを検討した（第2群）。その結果、9つmiRと15つのisomiRで再現性が確認された。多変量解析の結果から24の候補のうちmiR-30a-5p、isomiR-574-3p(3’deletionA)、isomiR-205-5p(3’deletionG)の3つを用いて診断パネルを作成した。診断パネルから計算されるパネルインデックスはESCC群でHC群より有意に高値であった(13.3±8.9vs.3.1±1.3、p<0.001)。 第 1 群、2 群を合わせた集団で ESCC を予測する ROC 曲線の AUC は 0.95 で感度 93.8%、特 異度 81%であった。この診断パネルの有用性を異なる患者群（ESCC18 例、HC18 例；第 3 群）で検証したところ感度 88.9%、特異度 72%であった。

同時期に採取した食道腺癌、食道高度異形成の患者ではパネルインデックスはそれぞれ 6.2±4.5、4.2±1.7 であり ESCC 群より有意に低く、HC 群と有意差を認めなかった。 治療後も血清検体が採取されていた 22例においてパネルインデックスは低下している傾 向を認めた(治療前 11.6±11.5 vs 6.2±5.6、p = 0.03)。

以上の結果から NGS により検出される血中 miRと isomiR を組み合わせることで食道扁 平上皮癌新規バイオマーカーとなる可能性が示唆された。

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