Long non-coding RNA growth arrest specific transcript 5 acts as a tumour suppressor in colorectal cancer by inhibiting interleukin-10 and vascular endothelial growth factor expression

Yuan Li,Yuhua Chen,Jiaming Qian,Mei Zhao,Caihong Zhou,Changzhi Huang,Shengkai Huang,Dongdong Li,Kun He,Hong Lin,Yan Li

doi:10.18632/oncotarget.14625

Yuan Li, Yuhua Chen + Show 9 more

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https://doi.org/10.18632/oncotarget.14625

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Long non-coding RNAs (lncRNAs) are highly involved in diverse biological processes of human malignancies. The expression profile and underlying mechanism of lncRNA growth arrest specific transcript 5 (GAS5) in colorectal cancer (CRC) is poorly understood. In this study, we found that GAS5 was commonly downregulated in CRC tissues, serum of CRC patients and CRC cell lines. Knockdown of GAS5 promoted CRC cell proliferation and colony formation, whereas overexpression of GAS5 produced the opposite result. We further demonstrated that knockdown of GAS5 increased the expression and secretion of interleukin-10 (IL-10) and vascular endothelial growth factor (VEGF-A) via NF-κB and Erk1/2 pathways. Neutralization of IL-10 and VEGF-A reduced tumour proli feration caused by GAS5 knockdown. Moreover, GAS5 expression showed a statistically significant correlation with the mRNA levels of IL-10 and VEGF-A in CRC tissues. We further illustrated that GAS5 was markedly downregulated and negatively correlated with the cytokine expression in a mouse model of colitis-associated cancer (CAC). These results delineate a novel mechanism of lncRNA GAS5 in suppressing colorectal carcinogenesis. The cytokines IL-10 and VEGF-A inhibited by GAS5 may provide targets for lncRNA-based therapies for CRC.

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Colorectal cancer (CRC) is the third most common cancer and the fourth most deadly cancer globally, accounting for approximately 1.2 million new cases and 600,000 deaths annually [1]
We further demonstrated that knockdown of growth arrest specific transcript 5 (GAS5) increased the expression and secretion of interleukin-10 (IL-10) and vascular endothelial growth factor (VEGF-A) via NF-κB and Erk1/2 pathways
An obvious correlation can be seen between GAS5 levels and lymph node invasion, as well as tumour node-metastasis (TNM) staging in patients with colorectal cancer (CRC); no significant correlation between GAS5 levels and sex, age, depth of invasion or tumour size was detected in patients with CRC (Table 1)

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Colorectal cancer (CRC) is the third most common cancer and the fourth most deadly cancer globally, accounting for approximately 1.2 million new cases and 600,000 deaths annually [1]. Most cases of CRC are sporadic and develop slowly over 10 years through the adenomacarcinoma sequence. The 5-year relative survival has reached nearly 65% in high-income countries but has remained under 50% in low-income countries [2]. In the past few decades, numerous molecular pathogenesis studies have indicated that the mutations in certain protein-coding genes (APC, KRAS, TP53) correlate with the pathogenesis of CRC [3, 4]. Recent advances have revealed that long non-coding RNAs (lncRNAs) are highly involved in the cancer paradigm [5]

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