Serine Threonine Kinase 17A Maintains the Epithelial State in Colorectal Cancer Cells

Abstract

Serine Threonine Kinase 17A (STK17A) is a ubiquitously expressed kinase originally identified as a regulator of apoptosis; however, whether it functionally contributes to colorectal cancer (CRC) has not been established. Here, we have analyzed STK17A in CRC and demonstrate decreased expression of STK17A in primary tumors which is further reduced in metastatic lesions, indicating a potential role in regulating the metastatic cascade. Interestingly, changes in STK17A expression did not modify proliferation, apoptosis, or sensitivity of CRC cell lines to treatment with the chemotherapeutic 5-fluorouracil. Instead, STK17A knockdown induced a robust mesenchymal phenotype consistent with the epithelial-mesenchymal transition, including spindle-like cell morphology, decreased expression of adherens junction proteins, and increased migration and invasion. Additionally, overexpression of STK17A decreased cell size and induced wide-spread membrane blebbing, a phenotype often associated with activation of cell contractility. Indeed, STK17A overexpressing cells displayed heighted phosphorylation of myosin light chain in a manner dependent on STK17A catalytic activity. Finally, patient-derived tumor organoid cultures were used to more accurately determine STK17A’s effect in primary human tumor cells. Loss of STK17A induced morphological changes, decreased E-cadherin, increased invasion, and augmented organoid attachment on 2D substrates, all-together suggesting a more metastatic phenotype. Collectively, these data indicate a novel role for STK17A in regulation of epithelial phenotypes and indicate its functional contribution to CRC invasion and metastasis. Implications: Loss of serine threonine kinase 17A occurs in colorectal cancer metastasis, induces mesenchymal morphologies, and contributes to tumor cell invasion and migration in colorectal cancer.

Biomarker roles identification of miR-106 family for predicting the risk and poor survival of colorectal cancer

“…Enrichment GO analysis also suggested that miR-106a and miR-106b were both mostly correlated with the vital cell components including nucleus, nucleoplasm and nucleolus, which have been demonstrated to be associated with the proliferation and invasion of CRC [42]. For MF, the targets of miR-106a and miR-106b were mainly linked with the binding function and enzyme activity, which has also been proved to be involved in the development and classification of CRC [43,44]. What's more, the KEGG pathway enrichment analysis revealed that some important pathways associated with miR-106a and miR-106b might take part in the pathogenesis of CRC according to literature exploration.…”

Improving the diversity of captured full-length isoforms using a normalized single-molecule RNA-sequencing method

“…TCGA data, however, reflected the increased expression of both IL32 and STK17A in STADs compared with non-malignant pairs at gene level, and the potential association of their expression with STAD prognosis. It should be noted that the expression patterns and prognostic association of STK17A in STADs were in contrast to other tumors 36 .…”

“…IL32 has been reported to relate with carcinogenesis, metastasis, angiogenesis, and regulation of the antitumor immune response in various tumors 35 . STK17A is a ubiquitously expressed kinase, which was reported to regulate apoptosis, epithelial phenotypes, etc., and showed suppression on tumor progression and invasion in several other tumors 36 . Neither IL32 nor STK17A showed apparent expression difference at gene level but both showed SRCC-specific isoforms, for which SGS short-read quantification also supported the substantial increase of expression in SRCCs at the isoform level (Fig.…”

Biomarker roles identification of miR-106 family for predicting the risk and poor survival of colorectal cancer

“…Enrichment GO analysis also suggested that miR-106a and miR-106b were both mostly correlated with the vital cell components including nucleus, nucleoplasm and nucleolus, which have been demonstrated to be associated with the proliferation and invasion of CRC [41]. For MF, the targets of miR-106a and miR-106b were mainly linked with the binding function and enzyme activity, which has also been proved to be involved in the development and classification of CRC [42,43].…”