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WiNTRLINC1/ASCL2/c-Myc Axis Characteristics of Colon Cancer with Differentiated Histology at Young Onset and Essential for Cell Viability

Kazuko Yokota MD, Yoko Tanaka MD, Hiroki Harada MD, Takeshi Kaida MD, Syuji Nakamoto MD, Takafumi Soeno MD, Yoshiki Fujiyama MD, Mitsuo Yokota MD, Ken Kojo MD, PhD, Hirohisa Miura MD, Takahiro Yamanashi MD, Takeo Sato MD, PhD, Takatoshi Nakamura MD, PhD, Masahiko Watanabe MD, PhD, FACS, Keishi Yamashita MD, PhD, FACS
Translational Research and Biomarkers
Volume 26, Issue 13 / December , 2019

Abstract

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 (c-Myc/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.

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