Translated Long Non-Coding Ribonucleic Acid ZFAS1 Promotes Cancer Cell Migration by Elevating Reactive Oxygen Species Production in Hepatocellular Carcinoma

Abstract

Micropeptides (≤100 amino acids) are essential regulators of physiological and pathological processes, which can be encoded by small open reading frames (smORFs) derived from long non-coding RNAs (lncRNAs). Recently, lncRNA-encoded micropeptides have been shown to have essential roles in tumorigenesis. Since translated smORF identification remains technically challenging, little is known of their pathological functions in cancer. Therefore, we created classifiers to identify translated smORFs derived from lncRNAs based on ribosome-protected fragment sequencing and machine learning methods. In total, 537 putative translated smORFs were identified and the coding potential of five smORFs was experimentally validated via green fluorescent protein-tagged protein generation and mass spectrometry. After analyzing 11 lncRNA expression profiles of seven cancer types, we identified one validated translated lncRNA, ZFAS1, which was significantly up-regulated in hepatocellular carcinoma (HCC). Functional studies revealed that ZFAS1 can promote cancer cell migration by elevating intracellular reactive oxygen species production by inhibiting nicotinamide adenine dinucleotide dehydrogenase expression, indicating that translated ZFAS1 may be an essential oncogene in the progression of HCC. In this study, we systematically identified translated smORFs derived from lncRNAs and explored their potential pathological functions in cancer to improve our comprehensive understanding of the building blocks of living systems

<p>The Long Noncoding RNA ZFAS1 Potentiates the Development of Hepatocellular Carcinoma via the microRNA-624/MDK/ERK/JNK/P38 Signaling Pathway</p>

“…Hepatocellular carcinoma (HCC), accounting for over 90% of all primary liver cancers, ranks the sixth most prevalent cancer in a world range. 1 The high HCC rates in parts of Asia majorly reflect the enhanced prevalence of chronic hepatitis B virus infection, with more than 8% of the population in this region chronically infected with the virus. 2 For all stages combined, liver cancer is among the cancer with the lowest survival rate (18%), highlighting the urgency to clarify novel mechanisms culminating in liver malignancy.…”

Antibody profiling of patients with prostate cancer reveals differences in antibody signatures among disease stages

“…While most would likely serve as negative controls as they would not be expected to encode gene products, other groups have shown that some lncRNAs may be translated into unstable peptides or even functional proteins, especially with the dysregulation induced by cancer. 40–42 Hence, we reasoned that a few might serve as antibody targets in patients with prostate cancer.…”

Functional Peptides Encoded by Long Non-Coding RNAs in Gastrointestinal Cancer

“…found that lncRNA ZFAS1 enhanced the proliferation of liver cancer by inhibiting miR-193a-3p ( 110 ). Recent research evidence has revealed that lncRNA ZFAS1 can encode a small peptide to down-regulate NADH dehydrogenase expression (NDUFA6, NDUFB11 and NDUFB4) to enhance ROS production, thus promoting cancer development ( 76 ).…”