WiNTRLINC1/ASCL2/c-Myc Axis Characteristics of Colon Cancer with Differentiated Histology at Young Onset and Essential for Cell Viability
WiNTRLINC1/ASCL2/c-Myc Axis Characteristics of Colon Cancer with Differentiated Histology at Young Onset and Essential for Cell Viability
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DOI：
10.1245/s10434-019-07780-3
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发表时间：
2019-12-01
影响因子：
3.7
通讯作者：
Yamashita, Keishi
中科院分区：
文献类型：
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作者：
Yokota, Kazuko;Tanaka, Yoko;Yamashita, Keishi
背景。 WiNTRLINC1 是一种长非编码 RNA (lncRNA)，在结直肠癌中通过 achaete-scute 复合体同源物 2 (ASCL2) 正向调节 Wnt 通路。最近报道 ASCL2 在化疗耐药中发挥关键作用，但 WiNTRLINC1/ASCL2 轴在结肠癌中的临床相关性仍然不清楚。患者和方法。在 40 个原发性结肠癌组织和相应的正常粘膜组织中，在信使 RNA (mRNA) 水平上研究了 WiNTRLINC1/ASCL2 的表达，以及 Wnt 相关基因 (cMyc/PRL-3) 和其他 lncRNA (H19、HOTAIR 和 MALAT1)。 WiNTRLINC1 的敲低实验阐明了其在表达和化疗耐药中的作用。结果。实时定量逆转录酶-聚合酶链反应证实，与相应的正常结肠粘膜组织（例如 ASCL2、c-Myc 和 PRL-3）（p < 0.0001）相比，原发性结肠癌中 WiNTRLINC1 mRNA 确实过表达（p = 0.0005）。临床样本中，四个基因表达特征与 ASCL2 基因中心紧密相关（r = 0.72，p < 0.0001）。 WiNTRLINC1 与结肠癌和其他 lncRNA 的预后因素没有显着相关，而 WiNTRLINC1/ASCL2/c-Myc 特征是具有分化组织学的年轻发病结肠癌所特有的。另一方面，未分化的组织学与 H19 表达显着相关。 WiNTRLINC1 基因的敲低降低了 ASCL2/c-Myc 的表达，但在 mRNA 水平上增强了 PRL-3，并强烈影响结肠癌细胞系中的细胞活力。结论。参与 Wnt 通路激活的增强的 WiNTRLINC1/ASCL2/c-Myc 轴是分化结肠肿瘤发生所必需的常见通路，尤其是年轻发病者，并且可能对于结肠癌的可行表型至关重要。
Background. WiNTRLINC1 is a long non-coding RNA (lncRNA) that positively regulates the Wnt pathway via achaete-scute complex homolog 2 (ASCL2) in colorectal cancer. ASCL2 was recently reported to play a critical role in chemoresistance, however clinical relevance of the WiNTRLINC1/ASCL2 axis remains obscure in colon cancer.Patients and Methods. WiNTRLINC1/ASCL2 expression was investigated at messenger RNA (mRNA) level in 40 primary colon cancer tissues and the corresponding normal mucosa tissues, together with Wnt-related genes (cMyc/PRL-3) and other lncRNAs (H19, HOTAIR, and MALAT1). Knock-down experiments of WiNTRLINC1 clarified its role in their expression and chemoresistance.Results. Real-time quantitative reverse transcriptase-polymerase chain reaction confirmed definite overexpression of WiNTRLINC1 mRNA in primary colon cancer compared with the corresponding normal colon mucosa tissues (p = 0.0005), such as ASCL2, c-Myc, and PRL-3 (p < 0.0001). The four gene expression signatures were tightly associated in the center of the ASCL2 gene (r = 0.72, p < 0.0001) in clinical samples. WiNTRLINC1 was not significantly associated with prognostic factors in colon cancer and other lncRNAs, while the WiNTRLINC1/ASCL2/c-Myc signatures were unique to young-onset colon cancer with differentiated histology. On the other hand, undifferentiated histology was significantly associated with H19 expression. Knockdown of the WiNTRLINC1 gene reduced the expression of ASCL2/c-Myc, but rather augmented PRL-3 at mRNA level, and robustly affected cell viability in colon cancer cell lines.Conclusion. The enhanced WiNTRLINC1/ASCL2/c-Myc axis involved in Wnt pathway activation is a common pathway essential for differentiated colon tumorigenesis, especially with young onset, and may be essential for a viable phenotype of colon cancer.