Abstract
Dedicator of cytokinesis 1 (DOCK1) is a critical regulator of cancer metastasis. Claudins are transmembrane proteins that play a role in epithelial barrier integrity. Due to a loss or low expression of claudins (CLDN), the claudin-low type of triple-negative breast cancer (TNBC) is characterized by a mesenchymal-like phenotype with strong metastatic potential. In order to elucidate the mechanism of DOCK1 in cancer metastasis, we first analyzed the transcriptomic changes using a clinical database of human TNBC and found that the increase in DOCK1 expression was highly correlated with the poor survival rate of TNBC patients. Interference with DOCK1 expression by shRNA resulted in re-expression of claudin-1 in conjunction with significant inhibition of cell viability and motility of claudin-low breast cancer cells. Accordingly, overexpression of claudin-1 suppressed cell viability and migration. Genetic knockdown and pharmacological blockade of Rac1/Rac2 up-regulated claudin-1. DOCK1 knockdown also caused a decrease in DNA methyltransferase (DNMT) expression and an increase in claudin-1 transcript and promoter activity. Furthermore, RRP1B mediated DOCK1 depletion, which up-regulated claudin-1 expression, cell viability, and motility in claudin-low breast cancer cells. This study demonstrated that DOCK1 mediates growth and motility through down-regulated claudin-1 expression via the RRP1B–DNMT–claudin-1 pathway and that claudin-1 serves as an important effector in DOCK1-mediated cancer progression and metastasis in claudin-low breast cancer cells.
Highlights
Breast cancer is the second leading cause of cancer-related death in women worldwide [1].Breast cancer is a genetically heterogeneous group of tumors and can be further subdivided intoCancers 2019, 11, 1762; doi:10.3390/cancers11111762 www.mdpi.com/journal/cancersCancers 2019, 11, 1762 several types, including luminal estrogen receptor- and progesterone receptor-positive (ER+ /PR+ ), human epidermal growth factor receptor 2 (HER2)-positive, and triple-negative (ER− /PR− /HER2− )cancers
We first investigated the correlation between the Dedicator of cytokinesis 1 (DOCK1) transcript level and the probability of survival of triple-negative breast cancer (TNBC) patients using the dataset from the Kaplan–Meier Plotter (Breast Cancer)
Results of Quantitative Real-Time Reverse Transcription PCR (qRT-PCR) analysis showed that claudin-1 transcript (CLDN1) levels were significantly increased by shDOCK1 intervention (Figure 6A), while moderate increases were observed in CLDN3, CLDN4, and CLDN7 expression (Figure 6B)
Summary
Breast cancer is the second leading cause of cancer-related death in women worldwide [1].Breast cancer is a genetically heterogeneous group of tumors and can be further subdivided intoCancers 2019, 11, 1762; doi:10.3390/cancers11111762 www.mdpi.com/journal/cancersCancers 2019, 11, 1762 several types, including luminal estrogen receptor- and progesterone receptor-positive (ER+ /PR+ ), human epidermal growth factor receptor 2 (HER2)-positive, and triple-negative (ER− /PR− /HER2− )cancers. The claudin-low subtype was newly identified within triple-negative breast cancer (TNBC), characterized by the low expression of tight junction and adherens proteins, including claudin-1, -3,. EMT is a critical process in cancer cells, during which their phenotype changes from a noninvasive phenotype into an invasive one and, during this process, cancer cells become anchorage-independent and exhibit dramatically enhanced motility and aggressiveness [5,6,7]. Due to the disruption of intracellular adhesion and enhanced motility, the loss of claudin-1 is associated with tumor cell invasiveness, high recurrence status, and a shorter recurrence-free survival in breast cancer [10], oral squamous cell carcinoma [11], and gastric carcinoma patients [11]. Claudin-1 has been regarded as a tumor suppressor in breast cancer due to its frequent down-regulation during tumor progression [10,12,13,14]
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