Murakami Takashi, Mitomi Hiroyuki, Tsugawa Naoki, Otsuki Yudai, Kamba Eiji, Kadomatsu Yuichiro, Hayashi Takuo, Saito Tsuyoshi, Shibuya Tomoyoshi, Yao Takashi, Nagahara Akihito
Department of Gastroenterology, Juntendo University Faculty of Medicine, Tokyo, Japan.
Department of Human Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Gastroenterol Res Pract. 2025 Jul 14;2025:1010891. doi: 10.1155/grp/1010891. eCollection 2025.
Colorectal carcinogenesis involves two distinct pathways, the serrated neoplasia pathway and adenoma (AD)-carcinoma sequence, whose precursors are sessile serrated lesion (SSL) and traditional AD, respectively. MicroRNAs (miRNAs) regulate gene expression and play a crucial role in colorectal tumorigenesis. This study investigated miRNA expression in the precursors and early invasive carcinomas of the two pathways. Using real-time reverse transcription polymerase chain reaction, we quantified the expression of miR-20a, miR-21, miR-93, and miR-181b in 127 lesions, including 25 SSLs, 19 SSLs with high-grade dysplasia (SSL-HD), 13 SSLs with submucosal invasive carcinoma (SSL-SC), 19 ADs, 26 ADs with HD (AD-HD), and 25 ADs with SC (AD-SC). In the SSL series, miR-93 (SSL vs. SSL-SC, = 0.038) and miR-181b (SSL vs. SSL-HD/SSL-SC, = 0.013/ < 0.001, respectively) levels decreased with tumor progression. In the AD lineage, the expression of miR-20a (AD vs. AD-SC and AD-HD vs. AD-SC, < 0.001), miR-21 (AD vs. AD-HD/AD-SC and AD-HD vs. AD-SC, < 0.001), and miR-181b (AD-HD vs. AD-SC, = 0.020) increased during carcinogenesis. Compared with normal mucosa (baseline), miR-93 expression showed a stepwise increase with tumor progression in the AD lineage, whereas the values did not change during SSL carcinogenesis. In the AD lineage, miR-20a expression increased in early invasive carcinoma but decreased in this phase of the SSL series. Overall, miR-20a, miR-93, and miR-181b levels were significantly lower in SSL-SC than in AD-SC (all < 0.001). These findings indicate that the SSL and AD pathways exhibit distinct miRNA expression dynamics during colorectal tumorigenesis, with the AD lineage showing a progressive increase in oncogenic miRNAs and the SSL series exhibiting selective downregulation or plateauing, particularly in invasive lesions. The differential expression of miR-20a, miR-21, miR-93, and miR-181b was presumed to be related to (epi)genetic alterations among serrated neoplasia and AD-carcinoma routes.
结直肠癌发生涉及两条不同的途径，即锯齿状肿瘤形成途径和腺瘤（AD）-癌序列，其前体分别为无蒂锯齿状病变（SSL）和传统AD。微小RNA（miRNA）调节基因表达，并在结直肠癌发生中起关键作用。本研究调查了这两条途径的前体和早期浸润性癌中的miRNA表达。使用实时逆转录聚合酶链反应，我们定量了127个病变中miR-20a、miR-21、miR-93和miR-181b的表达，包括25个SSL、19个高级别异型增生的SSL（SSL-HD）、13个伴有黏膜下浸润癌的SSL（SSL-SC）、19个AD、26个伴有HD的AD（AD-HD）和25个伴有SC的AD（AD-SC）。在SSL系列中，miR-93（SSL与SSL-SC相比，P = 0.038）和miR-181b（SSL与SSL-HD/SSL-SC相比，P分别为0.013/<0.001）水平随肿瘤进展而降低。在AD谱系中，miR-20a（AD与AD-SC以及AD-HD与AD-SC相比，P<0.001）、miR-21（AD与AD-HD/AD-SC以及AD-HD与AD-SC相比，P<0.001）和miR-181b（AD-HD与AD-SC相比，P = 0.020）在癌变过程中表达增加。与正常黏膜（基线）相比，miR-93表达在AD谱系中随肿瘤进展呈逐步增加，而在SSL癌变过程中其值没有变化。在AD谱系中，miR-20a表达在早期浸润性癌中增加，但在SSL系列的这一阶段降低。总体而言，SSL-SC中miR-20a、miR-93和miR-181b水平显著低于AD-SC（均P<0.001）。这些发现表明，在结直肠癌发生过程中，SSL和AD途径表现出不同的miRNA表达动态，AD谱系中致癌miRNA呈逐渐增加，而SSL系列表现出选择性下调或趋于平稳，尤其是在浸润性病变中。推测miR-20a、miR-21、miR-93和miR-181b的差异表达与锯齿状肿瘤形成和AD-癌途径之间的（表观）遗传改变有关。
