Epithelial Cancer Invasion Research Articles

STK11 Loss: A Novel Mechanism for Melanoma Metastasis with Therapeutic Implications

STK11 is implicated as a tumor suppressor in epithelial cancer invasion and metastasis. In their new article in the Journal of Investigative Dermatology, Dzung etal. (2021) show that loss of STK11 in cutaneous melanoma cells leads to an invasive metastatic phenotype through the activation of the signal transducer and activator of transcription (STAT) 3/5 and FAK signaling pathways. These results suggest that inhibition of STAT3/5 and FAK in STK11-deficient melanoma cells could serve as a novel therapeutic strategy against metastatic melanoma.

MiR-204-5p/Six1 feedback loop promotes epithelial-mesenchymal transition in breast cancer.

Epithelial-mesenchymal transition (EMT) is a vital process in epithelial cancer invasion and metastasis. The induction of EMT by Six1 has been described as a common mode of cancer progression, which could promote breast cancer migration and invasion. In the study, we found that miR-204-5p could suppress the migration and invasion of breast cancer cell lines. Since overexpression of Six1 promote EMT, we identified a mechanism by which miR-204-5p inhibited the EMT by downregulating the Six1, which was mediated by a conserved miR-204-5p seed-matching sequence in the 3'-UTR of Six1 mRNA. We also identified that upregulation of Six1 could downregulate miR-204-5p expression, affecting the migration and invasion of breast cancer cell lines. In conclusion, the frequent upregulation of Six1 and/or downregulation of miR-204-5p in breast cancer may shift the equilibrium of these reciprocal regulations and lock breast cancer cells in the mesenchymal state.

MiR-153 inhibits epithelial-mesenchymal transition by targeting metadherin in human breast cancer.

Epithelial-mesenchymal transition (EMT) is a crucial step in epithelial cancer invasion and metastasis. miR-153 has been identified as a key EMT suppressor. Accordingly, this study aimed to determine the possible relation of miR-153 downregulation to EMT through MTDH modulation. The miR-153 and MTDH expression profiles of human breast cancer specimen were determined by qPCR and evaluated by correlation analysis. Cell viability and clonogenic assays were applied to explore the impact of miR-153 on suppression of proliferation and oncogenic potential of breast cancer cells. Cell migration and invasion assays were used for the functional analysis of miR-153 in MCF-7 and MDA-MB-231 cells. Luciferase assay was adopted to identify MTDH as a new direct target of miR-153. Ectopic expression of miR-153 could significantly inhibit tumor growth and impair the migration and invasion of breast cancer cells. Overexpression of miR-153 simultaneously increased E-cadherin, decreased vimentin expression, and downmodulated EMT-associated transcription factors. miR-153 was negatively correlated with MTDH in cell lines and clinical samples. Overexpression of miR-153 significantly suppressed MTDH, as demonstrated by in vitro MTDH 3'-untranslated region luciferase report assay. MTDH is a direct downstream target of miR-153 and is involved in the miR-153-induced suppression of the migration and invasion of breast cancer cells. Our findings indicate that miR-153 functions as a tumor suppressor and miR-153/MTDH link is a promising therapeutic target for breast cancer.

Downregulation of miR-153 contributes to epithelial-mesenchymal transition and tumor metastasis in human epithelial cancer

The epithelial-mesenchymal transition (EMT) is a crucial step in epithelial cancer invasion and metastasis. The aims of this study were to investigate and validate unidentified micro RNAs (miRNAs) that regulate EMT and to reveal their clinical relevance in epithelial cancer patients. By applying miRNA array screening in a natural epithelial-mesenchymal phenotype cell line pair and in a transforming growth factor β-induced EMT cell model, we found miR-153 was markedly downregulated in the cells that underwent an EMT. A close association was confirmed between inhibition of miR-153 and the EMT phenotype, as well as the invasive ability of epithelial cancer cells. Ectopic expression of miR-153 in mesenchymal-like cells resulted in an epithelial morphology change with decreased cellular invasive ability. On the contrary, transfection of a miR-153 inhibitor in epithelial-like cells led to a mesenchymal phenotype change. In vivo ectopic expression of miR-153 significantly inhibited tumor cell metastasis formation. Data from the dual-luciferase reporter gene assay showed, for the first time, that SNAI1 and ZEB2 were direct targets of miR-153. Inverse correlations were also observed between miR-153 and SNA1 and ZEB2 levels in oral cancer patients' samples. Furthermore, low expression level of miR-153 was found to be significantly related to metastasis and poor prognosis in oral cancer patients. These data demonstrate that miR-153 is a novel regulator of EMT by targeting SNAI1 and ZEB2 and indicate its potential therapeutic value for reducing cancer metastasis.

T Cell-Derived Matrix Metalloproteinase-9 in Breast Cancer: Friend or Foe?

It has been reported that in epithelial cancer invasion, most matrix metalloproteinases (MMPs) are made by stromal cells of the host, and not the neoplasm itself. Findings from several laboratories indicate that immune cell-derived MMPs may be advantageous to developing tumors by promoting angiogenesis, neoplastic cell proliferation, and progression to malignancy. We have found a dramatic up-regulation of MMP-9 secretion by splenic and tumor-infiltrating T lymphocytes from D1-DMBA-3 mammary tumor-bearing mice compared to T cells from normal animals. Furthermore, tumor-derived vascular endothelial growth factor induced the up-regulation of MMP-9 in T cells, corroborating the suggestion that tumor cells may "conscript" inflammatory cells to make contributions to the tumor phenotype. Some investigators propose that the resulting degradation of the extracellular matrix by lymphocyte-derived proteases might be used by tumor cells to establish a blood supply and to metastasize. The outcome of MMP activity in the tumor microenvironment may be dependent on a variety of factors including tumor phenotype; the presence of other proteases and cytokines; and the time, level, and site of MMP production. In light of recent findings that MMPs are also capable of generating anti-angiogenic molecules, further investigation will bear out whether inflammatory cell-derived MMPs are friend or foe to developing tumors.

Critical role of N-cadherin in myofibroblast invasion and migration in vitro stimulated by colon-cancer-cell-derived TGF-beta or wounding.

Invasion of stromal host cells, such as myofibroblasts, into the epithelial cancer compartment may precede epithelial cancer invasion into the stroma. We investigated how colon cancer-derived myofibroblasts invade extracellular matrices in vitro in the presence of colon cancer cells. Myofibroblast spheroids invade collagen type I in a stellate pattern to form a dendritic network of extensions upon co-culture with HCT-8/E11 colon cancer cells. Single myofibroblasts also invade Matrigel trade mark when stimulated by HCT-8/E11 colon cancer cells. The confrontation of cancer cells with extracellular matrices and myofibroblasts, showed that cancer-cell-derived transforming growth factor-beta (TGF-beta) is required and sufficient for invasion of myofibroblasts. In myofibroblasts, N-cadherin expressed at the tips of filopodia is upregulated by TGF-beta. Functional N-cadherin activity is implicated in TGF-beta stimulated invasion as evidenced by the neutralizing anti-N-cadherin monoclonal antibody (GC-4 mAb), and specific N-cadherin knock-down by short interference RNA (siRNA). TGF-beta1 stimulates Jun N-terminal kinase (also known as stress-activated protein kinase) (JNK) activity in myofibroblasts. Pharmacological inhibition of JNK alleviates TGF-beta stimulated invasion, N-cadherin expression and wound healing migration. Neutralization of N-cadherin activity by the GC-4 or by a 10-mer N-cadherin peptide or by siRNA reduces directional migration, filopodia formation, polarization and Golgi-complex reorientation during wound healing. Taken together, our study identifies a new mechanism in which cancer cells contribute to the coordination of invasion of stromal myofibroblasts.

Expression and Tyrosine Phosphorylation of E-Cadherin, β- and γ-Catenin, and Epidermal Growth Factor Receptor in Cervical Cancer Cells

Objectives. The cadherin/catenin adhesion complex is fundamentally involved in epithelial cancer invasion and metastasis. Much evidence suggesting that epidermal growth factor (EGF) induced the scattering and invasion of cancer cells, probably by affecting E-cadherin function, has been reported. The present study aimed to confirm the hypothesis that EGF/epidermal growth factor receptor (EGFR) was related with the E-cadherin adhesion system in cervical cancer cells and that EGF might induce tyrosine phosphorylation of β- and γ-catenin.Methods. Cervical cancer cells were treated for different time durations with 30 ng/ml of EGF. Alteration of the cell morphology was examined by light microscopy and the expression of E-cadherin, β-catenin, γ-catenin, EGFR, and activated EGFR was assayed using Western blotting. Tyrosine phosphorylation of β- and γ-catenin was also examined using immunoprecipitation.Results. E-cadherin and EGFR were expressed in CaSki, HT-3, and ME-180 cell lines, which showed epithelial contact growth. The expression of E-cadherin and β- and γ-catenin did not change after treatment with EGF. The expression of EGFR decreased and activated EGFR expression increased in 30 min and then decreased subsequently. The simultaneous expression of activated EGFR and tyrosine phosphorylation of β- and γ-catenin was found.Conclusions. EGF-induced scattering of the E-cadherin-positive cervical cancer cells might be the result of tyrosine phosphorylation of the β- and γ-catenin. Phosphorylation of the β- and γ-catenin may hamper the adhesive function of the E-cadherin–catenin complex.