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SOX9 [sex-determining region Y (SRY)-box 9 protein], a high mobility group box transcription factor, plays critical roles during embryogenesis and its activity is required for development, differentiation, and lineage commitment in various tissues including the intestinal epithelium. Here, we present functional and clinical data of a broadly important role for SOX9 in tumorigenesis. SOX9 was overexpressed in a wide range of human cancers, where its expression correlated with malignant character and progression. Gain of SOX9 copy number is detected in some primary colorectal cancers. SOX9 exhibited several pro-oncogenic properties, including the ability to promote proliferation, inhibit senescence, and collaborate with other oncogenes in neoplastic transformation. In primary mouse embryo fibroblasts and colorectal cancer cells, SOX9 expression facilitated tumor growth and progression whereas its inactivation reduced tumorigenicity. Mechanistically, we have found that Sox9 directly binds and activates the promoter of the polycomb Bmi1, whose upregulation represses the tumor suppressor Ink4a/Arf locus. In agreement with this, human colorectal cancers showed a positive correlation between expression levels of SOX9 and BMI1 and a negative correlation between SOX9 and ARF in clinical samples. Taken together, our findings provide direct mechanistic evidence of the involvement of SOX9 in neoplastic pathobiology, particularly, in colorectal cancer. Cancer Res; 72(5); 1301–15. ©2012 AACR.

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Single-nucleotide resolution, high throughput and excellent precision make small RNA sequencing ideally suited for addressing a wide array of microRNA (miRNA) research questions. It is however known that adapter ligation introduces bias distorting the relation between sample expression levels and sequencing read counts. To investigate how this issue may affect studies aiming to identify miRNA biomarkers, we utilized the recently published High Definition library preparation protocol to generate miRNA profiles of 35 colorectal cancer cell lines, 55 primary cancer biopsies and 5 adjacent normal mucosa samples. The protocol minimizes ligation bias by means of randomized adapter pools. Comparing the resulting data against publicly available colorectal cancer miRNA datasets, we demonstrate that the High Definition protocol moderates read count distributions, increases accuracy and improves sensitivity while maintaining high reproducibility. Moreover, by taking advantage of the more quantitative read counts, the cancer cell line panel and the normal mucosa samples, we identify a set of miRNAs that are highly expressed in epithelial cancerous cells, deregulated in colorectal cancer as compared to normal mucosa and differentially expressed between established molecular subgroups. As such, these miRNAs present strong candidates for functional validation and biomarker testing. In conclusion, we here present High Definition miRNA sequencing data for a large panel of clinically relevant colorectal cancer samples highlighting the potential of improved small RNA library preparation methods. Citation Format: Peter W. Eide, Lina Cekaite, Ping Xu, Leonardo A. Meza-Zepeda, Tamas Dalmay, Ragnhild A. Lothe. Randomized adapter pools for microRNA sequencing of colorectal cancer cell lines and primary tumors. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A44.