Sugai Tamotsu, Osakabe Mitsumasa, Niinuma Takeshi, Sugimoto Ryo, Eizuka Makoto, Tanaka Yoshihito, Yanagawa Naoki, Otsuka Koki, Sasaki Akira, Matsumoto Takayuki, Suzuki Hiromu
Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun'yahabachou, Japan.
Department of Molecular Biology, Sapporo Medical University, School of Medicine, Sapporo, Japan.
Front Oncol. 2022 Jul 7;12:831100. doi: 10.3389/fonc.2022.831100. eCollection 2022.
Although MicroRNAs (miRNAs) play important roles in various biological processes, the biological functions of miRNAs are achieved through mRNAs. The aim of this study is to identify dysregulated miRNA/mRNA expression patterns in colorectal tumors.
We examined 42 colorectal tumors [15 adenomas, 8 intramucosal cancers (IMCs), and 19 invasive colorectal cancers (CRCs)] with the microsatellite stable (MSS) phenotype (first cohort). The first cohort was used for genome-wide miRNA and mRNA expression arrays, whereas the second cohort (37 colorectal neoplasias) was used for validation analyses. Finally, we used 15 cases of "adenoma in/with carcinoma" to identify network patterns of miRNAs/mRNAs that were directly associated with neoplastic progression. In addition, simple regression analysis for array-based and RT-PCR analyses was performed to select candidate miRNA-mRNA pairs. Transfection of miRNA mimics was also performed to confirm whether target mRNA expression is affected by specific miRNAs.
Specific paired miRNA/mRNA networks, including hsa-miR-34a-5p/SLC12A2, hsa-miR-15b-5p/SLC12A2, hsa-miR-195-5p/SLC12A2, hsa-miRNA-502-3p/OLFM4, hsa-miRNA-6807-5p/ZG16, and hsa-miRNA 3064-5p/SH3BGRL3, were identified in samples of adenoma, IMC, and CRC with the MSS phenotype. In adenomatous lesions obtained from the same tumor with a carcinomatous lesion, we identified pairs of miRNA-130a-3p/HSPA8 and miRNA-22-3p/RP53 that were linked to multiple pathways. On the other hand, 2 pairs of miRNA/mRNA (miRNA-660-5p and miRNA-664a-5p/APP) were found in isolated carcinomatous glands. Ectopic expression of miRNA 3064-5p suppressed SH3BGRL3 expression.
We found that networks based on specific pairs of miRNAs/mRNAs contribute to progression from adenomatous and carcinomatous lesions. Our results provide insights into the molecular tumorigenesis of colorectal tumors.
尽管微小RNA（miRNA）在各种生物学过程中发挥着重要作用，但其生物学功能是通过信使核糖核酸（mRNA）实现的。本研究旨在识别结直肠肿瘤中失调的miRNA/mRNA表达模式。
我们检测了42例具有微卫星稳定（MSS）表型的结直肠肿瘤[15例腺瘤、8例黏膜内癌（IMC）和19例浸润性结直肠癌（CRC）]（第一队列）。第一队列用于全基因组miRNA和mRNA表达阵列分析，而第二队列（37例结直肠肿瘤）用于验证分析。最后，我们使用15例“腺瘤内/伴癌”病例来识别与肿瘤进展直接相关的miRNA/mRNA网络模式。此外，还进行了基于阵列和逆转录-聚合酶链反应（RT-PCR）分析的简单回归分析，以选择候选miRNA-mRNA对。还进行了miRNA模拟物转染，以确认靶mRNA表达是否受特定miRNA影响。
在具有MSS表型的腺瘤、IMC和CRC样本中，鉴定出特定的配对miRNA/mRNA网络，包括hsa-miR-34a-5p/SLC12A2、hsa-miR-15b-5p/SLC12A2、hsa-miR-195-5p/SLC12A2、hsa-miRNA-502-3p/OLFM4、hsa-miRNA-6807-5p/ZG16和hsa-miRNA 3064-5p/SH3BGRL3。在同一肿瘤的癌性病变中获得的腺瘤性病变中，我们鉴定出与多种途径相关的miRNA-130a-3p/HSPA8和miRNA-22-3p/RP53对。另一方面，在孤立的癌性腺管中发现了2对miRNA/mRNA（miRNA-660-5p和miRNA-664a-5p/APP）。miRNA 3064-5p的异位表达抑制了SH3BGRL3的表达。
我们发现基于特定miRNA/mRNA对的网络有助于腺瘤性和癌性病变的进展。我们的结果为结直肠肿瘤的分子肿瘤发生提供了见解。
