Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression

Abstract

Metastatic disease is a primary cause of cancer-related death, and factors governing tumor cell metastasis have not been fully elucidated. Here, we address this question by using tumor cell lines derived from mice that develop metastatic lung adenocarcinoma owing to expression of mutant K-ras and p53. Despite having widespread somatic genetic alterations, the metastasis-prone tumor cells retained a marked plasticity. They transited reversibly between epithelial and mesenchymal states, forming highly polarized epithelial spheres in threedimensional culture that underwent epithelial-to-mesenchymal transition (EMT) following treatment with transforming growth factor-b or injection into syngeneic mice. This transition was entirely dependent on the microRNA (miR)-200 family, which decreased during EMT. Forced expression of miR-200 abrogated the capacity of these tumor cells to undergo EMT, invade, and metastasize, and conferred transcriptional features of metastasis-incompetent tumor cells. We conclude that tumor cell metastasis is regulated by miR-200 expression, which changes in response to contextual extracellular cues. Lung cancer is the leading cause of cancer-related death in Western countries, and metastasis is the most common cause of death in patients with lung cancer. Approximately two-thirds of patients are diagnosed at an advanced stage, and of the remaining patients who undergo surgery, 30%-50% develop recurrence with metastatic disease. The lack of curative treatment options emphasizes the need for a better understanding of the biologic processes that drive metastasis. Toward that goal, genetic mouse models have been generated that develop lung adenocarcinoma, the most common histologic subtype of lung cancer, with differing propensities to invade and metastasize (Liu et al.

Control of EVI-1 oncogene expression in metastatic breast cancer cells through microRNA miR-22

“…One example is miR-200a. Reduced expression of miR-200a in primary tumors is essential for cancer cells to acquire invasive phenotype through epithelial-to-mesenchymal transition (Gibbons et al, 2009), whereas its overexpression in mammary tumor cell lines enhances mesenchymal-to-epithelial transition and increases macrometastasis (Dykxhoorn et al, 2009). Consistent with this possibility, we observed elevated miR-200a in metastatic cancer cells compared with parental cells or TMD-231 cells.…”

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

“…Chen et al [131] demonstrated that miR-200 suppressed the epithelial to mesenchymal transition (EMT) process by targeting PD-L1 and thus delaying cancer progression in a mouse model. As shown before, miR-200 expression is downregulated in highly metastatic cancer cells [132,133]. By inducing its expression, a reversed EMT phenotype was induced with abolished invasion and metastasis formation.…”

MicroRNA-200c plays an oncogenic role in nasopharyngeal carcinoma by targeting PTEN

“…27 Meanwhile, miR-200 family also inhibits EMT by downregulating ZEB1 and ZEB2. [28][29][30] These studies all suggest anti-cancer roles of miR-200 family. In addition, miR200a was also reported to be downregulated in NPC samples compared with adjacent normal tissues.…”