Purpose: Among small non-coding RNAs, micro-RNAs have demonstrated a variety of essential functions under both physiological and pathological conditions such as cell cycle progression, oncogenic transformation and apoptosis. Thus, we hypothesized that micro-RNAs may play a major role in cellular stress adaptation.

Methods: To attain this aim, we evaluated a multi-stage colon cancer system with increasing degrees of resistance to the antimetabolite 5-fluorouracil by i) differential expression profiling (micro-RNA arrays) and ii) subsequent validation of the candidate RNAs by quantitative PCR.

Results: Among 15 differential expressed micro-RNAs in our model system, 9 were confirmed by qPCR and selected for further investigations. Noteworthy, for every level of drug resistance (low, intermediate, and high) specific micro-RNAs were identified indicating an individual response to escalating cytotoxic stress at the molecular level. With regard to micro-RNA functions, our findings point at an involvement - if not a regulatory function - of the recognized micro-RNAs in the following processes (data from the literature): doxorubicin resistance (miR-130a), survival signaling, DNA-oriented stress, and oncogenic properties (all miR-19), epithelial-mesenchymal transition (miR-141 and miR-200), as well as invasion and metastasis (miR-10b). Some of these features are currently under investigation by transfection of the corresponding micro-RNA precursors or antagomirs in the chemoresistant model in order to assess the contribution of the identified micro-RNAs to the resistance phenotype.

Conclusions: Previous work from our team has demonstrated the orchestrated response of cancer cells to xenobiotics at the molecular level by global gene expression profiling. The investigated subclones, derived from the metastatic colon cancer cell line CCL 227, were characterized by stage dependent mRNA regulations affecting vital cellular functions such as cytoskeleton, cell-cell communication, signal transduction, cell cycle control and apoptosis. Remarkably, different degrees of chemoresistance addressed different cellular mechanisms, thus providing to the cancer cell the necessary flexibility to adapt to different levels of stress. Likewise, micro-RNAs seem to follow a similar behavior with different micro-RNA patterns reflecting the development of resistance to 5-fluorouracil. As micro-RNAs are very likely to play a decisive role in the cellular response to therapeutic stress, their regulation might offer novel starting points to understand and to oppose drug resistance. This work has been supported by the “Initiative Krebsforschung”, Austria.

Citation Information: Clin Cancer Res 2010;16(7 Suppl):A12