Abstract
Simple SummaryColorectal cancer is one of the most frequent types of cancer world-wide, leading to over 500,000 cancer-related deaths each year. Although many primary colorectal cancer patients can be cured by surgery, up to 60% will develop metastases. Chemotherapeutic strategies are well-established, but finally often lead to chemo-resistance and tumor relapse. A specific chemotherapeutic approach is low dose metronomic (LDM) therapy, which is based on a constant administration of low doses of a chemotherapeutic compound instead of high-dose pulses, which are often a huge burden for patients and also may induce rapid resistance. However, the molecular mechanism of LDM chemotherapy is not fully understood. Our study therefore aims at identifying gene signatures of colorectal cancer progression under LDM chemotherapy which eventually provides new potential biomarkers for therapeutic interventions.Understanding the molecular signatures of colorectal cancer progression under chemotherapeutic treatment will be crucial for the success of future therapy improvements. Here, we used a xenograft-based mouse model to investigate, how whole transcriptome signatures change during metastatic colorectal cancer progression and how such signatures are affected by LDM chemotherapy using RNA sequencing. We characterized mRNAs as well as non-coding RNAs such as microRNAs, long non-coding RNAs and circular RNAs in colorectal-cancer bearing mice with or without LDM chemotherapy. Furthermore, we found that circZNF609 functions as oncogene, since over-expression studies lead to an increased tumor growth while specific knock down results in smaller tumors. Our data represent novel insights into the relevance of non-coding and circRNAs in colorectal cancer and provide a comprehensive resource of gene expression changes in primary tumors and metastases. In addition, we present candidate genes that could be important modulators for successful LDM chemotherapy.
Highlights
Low-dose metronomic (LDM) chemotherapy, a regular administration of chemotherapeutic agents at low doses with close intervals over prolonged periods of time, is an emerging form of cancer therapy [1,2,3]
LINC01133 has no coding potential, we show that LINC00483 contains an open reading frames (ORF) and may have coding potential, suggesting that microproteins could play a role during cancer progression and therapy response
To find candidate coding and non-coding RNAs including miRNAs, lncRNA and circRNAs, and to unravel their molecular functions during colorectal cancer progression, we utilized a xenograft mouse model based on implantation of the HT29.hCG.Luc colorectal cancer cell line [19]
Summary
Low-dose metronomic (LDM) chemotherapy, a regular administration of chemotherapeutic agents at low doses with close intervals over prolonged periods of time, is an emerging form of cancer therapy [1,2,3]. Similar to other anticancer therapies, LDM chemotherapy often results in the development of resistance [8]. Numerous preclinical studies have identified molecular targets and pathways to understand the mechanism of LDM chemotherapy [1]. Known mechanisms of LDM chemotherapy include suppression of tumor-angiogenesis [1,9,10], depletion of regulatory T cells [10], direct tumor cell targeting effects [11,12] and the induction of tumor dormancy [2]. Some mechanisms that drive LDM chemotherapy resistance have been described. The detailed mechanism, is yet unknown [8,13,14]
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