Abstract
MicroRNAs (miRNAs) are master regulators of drug resistance and have been previously proposed as potential biomarkers for the prediction of therapeutic response in colorectal cancer (CRC). Sorafenib, a multi-kinase inhibitor which has been approved for the treatment of liver, renal and thyroid cancer, is currently being studied as a monotherapy in selected molecular subtypes or in combination with other drugs in metastatic CRC. In this study, we explored sorafenib-induced cellular effects in Kirsten rat sarcoma viral oncogene homolog olog (KRAS) wild-type and KRAS-mutated CRC cell lines (Caco-2 and HRT-18), and finally profiled expression changes of specific miRNAs within the miRNome (>1000 human miRNAs) after exposure to sorafenib. Overall, sorafenib induced a time- and dose-dependent growth-inhibitory effect through S-phase cell cycle arrest in KRAS wild-type and KRAS-mutated CRC cells. In HRT-18 cells, two human miRNAs (hsa-miR-597 and hsa-miR-720) and two small RNAs (SNORD 13 and hsa-miR-3182) were identified as specifically sorafenib-induced. In Caco-2 cells, nine human miRNAs (hsa-miR-3142, hsa-miR-20a, hsa-miR-4301, hsa-miR-1290, hsa-miR-4286, hsa-miR-3182, hsa-miR-3142, hsa-miR-1246 and hsa-miR-720) were identified to be differentially regulated post sorafenib treatment. In conclusion, we confirmed sorafenib as a potential anti-neoplastic treatment strategy for CRC cells by demonstrating a growth-inhibitory and cell cycle–arresting effect of this drug. Changes in the miRNome indicate that some specific miRNAs might be relevant as indicators for sorafenib response, drug resistance and potential targets for combinatorial miRNA-based drug strategies.
Highlights
Colorectal cancer (CRC) is among the leading causes of cancer-related mortality worldwide, representing a major public health problem [1]
The Kirsten rat sarcoma viral oncogene homolog olog (KRAS) wild-type Caco-2 cell line was more sensitive to sorafenib than the KRAS-mutated HRT-18 cells
We investigated the mode of action and whether sorafenib could induce apoptosis in the HRT-18 and Caco-2 cells
Summary
Colorectal cancer (CRC) is among the leading causes of cancer-related mortality worldwide, representing a major public health problem [1]. CRC frequently arises from dysplastic adenomatous polyps, and the process of transformation to carcinoma involves several essential events [3] These are characterized by the activation of oncogenes such as KRAS (Kirsten rat sarcoma viral oncogene homolog), c-MYC (v-myc avian myelocytomatosis viral oncogene homolog), and NRAS (neuroblastoma RAS viral oncogene homolog), and by inactivation of tumor suppressor genes such as APC (adenomatous polyposis coli) or DNA repair genes [4]. Prior studies have found that miRNAs are involved in sorafenib resistance in hepatocellular carcinoma [24], and a pharmacological approach to manipulate those particular miRNAs was shown to overcome resistance in pre-clinical models and proposed combinatorial treatment options [13,25]. We investigated alterations in the miRNome in CRC cells following treatment with the anti-cancer drug sorafenib in order to describe for the first time in a descriptive manner the miRNA changes in CRC cell lines after sorafenib exposure
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