Colorectal cancer (CRC) is the fourth most common cancer globally and the third leading cause of cancer related deaths . An increasing age can elevate the probability of developing CRC as well as polyps, inflammatory bowel diseases, and hereditary factors in the patients’ anamnesis. The best chance for cure is provided by complete surgical resection of the tumor. However, despite the fact that novel diagnostic tools as well as improved treatment strategies have been emerged in the past years, prognosis of CRC patients with advanced and metastatic tumor stage still remains poor with an average survival of less than 30 months . Consequently, novel targeted therapeutic approaches are urgently needed. Therefore, it is essential to understand molecular mechanisms of CRC. Uncovering disease associated pathways as well as their regulation and interaction, and identifying prognostic biomarkers might provide starting points for targeted therapy with increased selectivity, efficiency and reduced toxicity. Research in CRC reveals potential target molecules including members of the CK1 family. CK1 family members have been described to influence the activity of key regulatory proteins and signal integration molecules including β-catenin, p53, and MDM2, thereby regulating Wnt-signaling, cell cycle progression, and apoptosis induction. Importantly, all these pathways are well known for their role in tumor development and progression. Accordingly, deregulation of CK1 expression and/or activity is directly linked to tumor development and progression and has already been reported in various tumor entities, highlighting CK1 isoforms as attractive targets in tumor therapy (reviewed in ).
Microarray data analyses from different cancer cell lines using CellMiner™ database indicate high-level expression of CK1α in various colon and rectum cancer cell lines . However, so far, the role of CK1α as a prognostic marker in CRC has not been reported. In this study, we investigated CK1α RNA expression in CRC as a potential prognostic biomarker by comparing RNA expression levels in colorectal tumor tissue and healthy bowel tissue. Our results revealed that CK1α expression levels are significantly increased in tumor tissue compared to normal tissue, consequently indicating that CK1α is involved in developing and/or proceeding malignant characteristics of tumor cells. Since we found low expression levels in surviving individuals, it might be hypothesized that increased CK1α expression levels correlate with poor prognosis of CRC patients. Survival analyses, including Kaplan-Meier estimations and Cox regression analyses revealed that high CK1α expression levels in tumors are significantly associated with poor overall survival rates of CRC patients, indicating that CK1α is an independent negative prognostic factor in CRC. Interestingly, CK1α expression levels appear to vary in different cancer entities. Therefore, it remains to be shown whether our finding may be transferable to other cancers and if so, to which cancers. For example melanoma cells or lung cancer cells possess low-level expression . Additionally, despite availability of comparable survival information a link between prognosis and CK1α expression levels cannot be transferred to every tumor entity. A significant influence of CK1α expression levels on survival rates is demonstrated amongst others in breast cancer, leukemia, multiple myeloma, lung cancer, and diffuse large B cell lymphoma. For instance, in diffuse large B cell lymphoma a prolonged survival is connected with low CK1α expression levels, whereas in lung cancer high-level expression of CK1α is linked to better outcome . This indicates that CK1α expression levels cannot be used as a general prognostic marker and have to be determined individually in every tumor entity. Our study identifies that CK1α expression influences the overall survival of colorectal cancer patients since patients with short survival times show a statistically significant higher CK1α expression. Thus, we have identified CK1α expression as potential diagnostic or therapeutic applicability for colorectal cancer. However, our data do not provide evidence that CK1α expression may influence the outcome of a certain therapy and can therefore not be used as a predictive marker.
We previously reported a prognostic relevance of CK1δ expression in CRC patients, especially for those with low-grade tumors (Grade 1, Grade 2) . In the present study we could show that high CK1α expression levels strongly correlate with poor survival in high-grade (Grade 3, Grade 4) CRC patients, indicating that CK1α might be used as a biomarker in poorly differentiated cancers, whereas CK1δ represents a prognostic marker in highly differentiated CRC.
Interestingly, we found lower levels of both CK1 isoforms in surviving patients, indicating an involvement of CK1α and CK1δ in malignancy-associated pathways resulting in poor prognosis. Since the APC/Wnt/β-catenin pathway is known to play a major role in colorectal carcinogenesis and since both CK1 isoforms play regulatory roles in Wnt signaling it can be speculated that overexpression of CK1α and δ leads to a Wnt/β-catenin-dependent malignant phenotype of colorectal tumor cells [15, 22, 23]. However, this hypothesis has to be investigated in future experiments unraveling the molecular mechanisms behind CK1α/δ related colorectal carcinogenesis.
Since increased expression levels are associated with poor survival rates, CK1α might represent an attractive drug target in new CRC therapy concepts. Intriguingly, the prognostic relevance of high CK1α expression was explicitly high in UICC II and UICC III stage CRC. This patient cohort usually undergoes surgical resection with a curative intent. However, these patients exhibit a high risk of tumor recurrence due to large primary tumors and/or lymph node metastases at time of diagnosis. Therefore, these patients usually received adjuvant treatment upon surgical resection to decrease risk of recurrence and prolong overall survival. Interestingly, within the cohort patients with poorer survival show higher CK1α expression. Consequently, patients with high CK1α expression are less likely to benefit from conventional adjuvant chemotherapy to prevent recurrence providing the chance for cure. Moreover, based on our findings it is important to characterize the effects of CK1α downregulation by CK1α specific inhibitors or biological tools to receive information whether these patients would benefit from a CK1α targeting therapy in regard to long-term survival, in particular in chemoresistant cancers. Recently, D4476 has been described as a potent inhibitor of CK1α [24,25,26], although previously having been described as CK1δ/ε specific inhibitor [27, 28]. Furthermore, the effects of the anticancer drug lenalidomide are partially due to the initiation of proteasomal degradation of CK1α [29, 30]. Nevertheless, additional pre-clinical and clinical testing of CK1α inhibitors or agents inducing CK1α degradation or inhibiting the interaction of CK1α with cellular proteins  are urgently needed to further investigate their therapeutic potential.
In accordance with the published data a tumor localization-dependent correlation between survival and kinase expression was detected . High-level CK1α expressing tumors of the right colon (right colon cancer, RCC) correlate with poor outcome of the patients, whereas overall survival is not affected by CK1α expression of left-sided tumors (left colon cancer, LCC). Several reports distinguish right and left colon by differences in their biological properties. It has been demonstrated that embryologic origin, vascular supply, as well as composition and density of immune cells and microbiota differ in right and in left colon . Furthermore, genes involved in tumorigenesis-associated signaling pathways, cell cycle, proliferation, cell death, stress response, DNA replication, and damage repair have been reported to be differentially expressed, consequently leading to different oncogenic patterns . According to Vogelstein’s adenoma-carcinoma sequence a stepwise pattern of mutational inactivation of tumor suppressors and activation of oncogenes initiates and proceeds to colorectal carcinogenesis . So far, the role of CK1 isoforms within this sequence is unknown but several reports suggest a role of CK1 in regulating p53 activity, which in turn is inactivated in the majority of high-grade colorectal cancers [15, 34]. Furthermore, differences in the microenvironment, especially the release of pro-inflammatory cytokines, mainly released by immune cells (e.g. neutrophils and M1 macrophages), pro-inflammatory adipocytokines (e.g. leptin, visfatin) and fatty acids secreted by adipocytes accelerate adenoma carcinoma transition and can significantly promote migration and invasion of CRC cells via induction of epithelial mesenchymal transition [35,36,37,38]. In this respect, it can be speculated that CK1α expression might be involved in regulating microenvironment and oncogenic pathways in particular important in right-sided colon carcinogenesis, especially against the background that CK1α expression is similar in LCC and RCC. In order to investigate the impact of CK1α on RCC tumorigenesis further studies are crucial.