ENC1 Facilitates Colorectal Carcinoma Tumorigenesis and Metastasis via JAK2/STAT5/AKT Axis-Mediated Epithelial Mesenchymal Transition and Stemness

Abstract

Ectodermal neural cortex 1 (ENC1) is an actin-binding protein and has been known to be upregulated in several cancers, but the molecular mechanisms through which it contributes to the pathology of CRC have largely been elusive. We utilized data mining and validated the aberrant expression of ENC1, following which phenotypic traits of malignancy were assessed in vitro. Ruxolitinib was used as a surrogate to compare the effects of ENC1 expression and silencing on the JAK-STAT-AKT pathway. In vivo models were employed to confirm the in vitro observations. Computation analysis, strengthened by in situ and in vitro data, confirmed the overexpression of ENC1 in CRC and predicted a poor prognosis, while enhanced cell proliferation, invasion, migration, EMT, and stemness were associated with ENC1 overexpression. Silencing of ENC1 downregulated the phenotypes. Additionally, silencing of ENC1 significantly reduced the activation of JAK2 and consequent activation of STAT5 and AKT comparable to ruxolitinib inhibition of JAK2. Silencing of ENC1 resulted in lesser tumor volumes and fewer numbers of tumors, in vivo. These data suggest that ENC1 induces CRC through the JAK2-STAT5-AKT axis. ENC1 is a suitable diagnostic marker for CRC detection, and ENC1 targeting therapies may suppress CRC progression.

Mechanisms of Natural Extracts of Andrographis paniculata That Target Lipid-Dependent Cancer Pathways: A View from the Signaling Pathway

“…The overphosphorylation of STAT5 in the hyper-expressed JAK2/STAT5 pathway in mice has been found to result in a higher survival rate for prostate cancer, and hence has the possibility of being metastatic [ 109 ]. Similar findings were described by Cui and colleagues (2021) in mice with colorectal cancer [ 110 ]. Earlier, Chui and colleagues (2019) discovered that the activation of the JAK/STAT pathway occurs due to downregulation of TfR1 both in vivo and in vitro.…”

Evaluation of potential anti-metastatic and antioxidative abilities of natural peptides derived from Tecoma stans (L.) Juss. ex Kunth in A549 cells

“…ENC1, an actin-binding protein that is essential for gastrulation and nerve formation ( Hernandez et al, 1997 ), has been reported to be overexpressed in the colon ( Cui et al, 2021 ), breast ( Zhou et al, 2020 ), and lung cancers ( Wu et al, 2021 ). A cohort study of TCGA dataset showed that overexpression of ENC1 is associated with tumor progression and poor prognosis.…”

“…A cohort study of TCGA dataset showed that overexpression of ENC1 is associated with tumor progression and poor prognosis. Suppression of ENC1 expression inhibits the growth, migration and invasion of colon, breast, and lung cancer cell lines ( Cui et al, 2021 ; Wu et al, 2021 ; Zhou et al, 2020 ). Moreover, the knockdown of ENC1 significantly down-regulates the expression of mesenchymal markers (matrix metalloproteinase and N-cadherin) and up-regulates the expression of epithelial marker (E-cadherin) in lung cancer cell lines ( Wu et al, 2021 ).…”

Bioinformatics and in-silico findings reveal medical features and pharmacological targets of biochanin A against colorectal cancer and COVID-19

“…Our results highlighted some important pathways such as cytokine-cytokine receptor interaction, PI3K-Akt signaling pathway, and JAK-STAT signaling pathway targeted by biochanin A through the control of gene clusters ( CCND1, IL1A, IL2, KCND1 , and EGFR ). These pathways have been reported to be associated with immune responses in the lung and the carcinogenicity of CRC [ 41 , 42 ]. Cytokine-cytokine receptor interaction is responsible for the regulation of the tumor microenvironment and tumor cells [ 43 ].…”