br Results br Discussion In this study
Discussion In this study, we found that ZNF280A was elevated in CRC tissues and a high expression of ZNF280A correlated with advanced clinicopathological features, poor prognosis, and disease progression in CRC patients. Furthermore, silencing ZNF280A attenuated proliferation and inhibited Melittin mg in CRC cells in vitro, and it suppressed tumorigenesis in vivo. Our results also demonstrated that ZNF280A inactivated Hippo signaling, which further promoted the progression of CRC. Therefore, our findings present a novel mechanism by which ZNF280A promotes the proliferation and tumorigenesis of CRC cells. Surprisingly, as a transcriptional factor containing the two contiguous Cys2His2 zinc-finger motif, less is understood about the biological role of ZNF280A in cancers. Through a high-density SNP array and gene expression-profiling analysis, Beà and colleagues have found that homozygous deletions of ZNF280A were found in mantle cell lymphoma; moreover, Gunn et al. used an oligonucleotide-based array comparative genome hybridiza (CGH) analysis to detect genomic imbalances in 187 chronic lymphocytic leukemia (CLL) cases, and they found that the deletion of ZNF280A was found in 28 cases (15%). Real-time qPCR showed that the mRNA expression level of ZNF280A was significantly lower in the deleted region compared to non-deleted cases. However, the clinical significance and functional role of ZNF280A were not investigated in these studies, even in the context of cancer. In this study, we found that ZNF280A expression was robustly increased in CRC tissues and a high expression of ZNF280A was positively associated with T, N, and M classifications; clinical stages; and poor prognosis and disease progression in CRC patients. Furthermore, our results demonstrated that silencing ZNF280A inhibited the proliferation and tumorigenesis of CRC cells in vitro and in vivo. Therefore, our findings determine the oncogenic role of ZNF280A in the development and progression of CRC. The Hippo-signaling pathway has been found to be frequently inactivated in multiple human cancer types,9, 10, 11 including CRC.17, 18, 19 Numerous studies have reported that the downregulation of the Hippo pathway components mammalian MST1/2 and LATS1/2 or the upregulation of YAP or TAZ consistently contributed to the inactivation of Hippo signaling, which further promoted the progression of CRC.24, 25, 26 In this study, we found that silencing ZNF280A repressed the HOP-Flash, but not HIP-Flash, luciferase reporter activity, indicating that silencing ZNF280A activated Hippo signaling in CRC cells. Western blot and RT-PCR analysis further revealed that silencing ZNF280A dramatically enhanced the phosphorylated levels of MST1 and LATS1 and downregulated YAP and TAZ expressions, as well as reduced the expression levels of multiple downstream genes of the Hippo pathway in CRC cells. Thus, our findings uncover a novel mechanism that ZNF280A promotes the progression of CRC via inactivating Hippo signaling. As mentioned above, ZNF280A was reported to be deleted in hematopoietic malignancies, including mantle cell lymphoma and chronic lymphocytic leukemia, suggesting that ZNF280A may function as a tumor suppressor in hematopoietic malignancies. Conversely, our results found that ZNF280A was significantly upregulated via our samples and TCGA analysis. Importantly, functional experiments showed that silencing ZNF280A inhibited the cell proliferation and tumorigenesis in CRC, demonstrating the oncogenic role of ZNF280A in CRC. Therefore, existing reports in combination with our findings imply that ZNF280A may play an opposite, even paradoxical role dependent on cancer type. However, the underlying mechanism responsible for ZNF280A overexpression in CRC remains unclear, which is a major drawback deserving further clarification in the future work.
Materials and Methods
Conflicts of Interest