Abstract
Simple SummaryChemotherapeutic agents including cisplatin promote tumor metastasis while inhibiting tumor growth, which still represents a major obstacle for some patients in clinical practices. This study demonstrated that cisplatin induced epithelial-mesenchymal transition and tumor metastasis in lung adenocarcinoma. Further bioinformatic analysis showed that DCBLD2 may play a key role in metastasis after platinum chemotherapy. In terms of mechanism, DCBLD2 stabilized β-catenin through phosphorylation and inactivation of GSK3β, leading to the disintegration of the destruction complex of β-catenin. The accumulated β-catenin transported to the nucleus and promoted the expression of metastasis-related genes. In addition, cisplatin markedly enhanced DCBLD2 (Discoidin, CUB and LCCL domain containing 2) expression via ERK/AP-1 axis. Importantly, DCBLD2-specific siRNAs encapsulated by nanoparticles strikingly inhibited cisplatin-induced metastasis in tumor-bearing mice. Taken together, DCBLD2 mediates cisplatin-induced metastasis and DCBLD2 inhibition is a promising treatment option for preventing chemotherapy-induced metastasis.Growing evidence suggests that cisplatin and other chemotherapeutic agents promote tumor metastasis while inhibiting tumor growth, which is a critical issue for certain patients in clinical practices. However, the role of chemotherapeutics in promoting tumor metastasis and the molecular mechanism involved are unclear. Here, we investigated the roles of cisplatin in promoting tumor metastasis in lung adenocarcinoma (LUAD). We demonstrated that cisplatin promoted epithelial-mesenchymal transition (EMT), cell motility, and metastasis in vitro and in vivo. The bioinformatic analysis and molecular biology approaches also indicated that DCBLD2 (Discoidin, CUB and LCCL domain containing 2) is a key gene that mediates cisplatin-induced metastasis. DCBLD2 stabilizes β-catenin by phosphorylating GSK3β and transporting accumulated β-catenin to the nucleus to promote the expression of EMT-related transcriptional factors (TFs), ultimately resulting in tumor metastasis. We also identified that cisplatin enhanced DCBLD2 expression by phosphorylating ERK and hence the AP-1-driven transcription of DCBLD2. Furthermore, DCBLD2-specific siRNAs encapsulated by nanocarriers prominently inhibit cisplatin-induced metastasis in vivo. Therefore, DCBLD2 plays a key role in cisplatin-induced metastasis in LUAD and is a potential target for preventing chemotherapy-induced metastasis in vivo.
Highlights
Lung cancer is the most frequently diagnosed cancer and the leading cause of cancerrelated mortality worldwide [1,2]
Patients often receive consolidation chemotherapy to reduce metastasis or recurrence caused by residual tumor cells after responding to sequential induction chemotherapy
We revealed that the continuous exposure of resistant cells to chemotherapy agents might induce epithelialmesenchymal transition (EMT) and increase the metastatic potential of remaining cells
Summary
Lung cancer is the most frequently diagnosed cancer and the leading cause of cancerrelated mortality worldwide [1,2]. Other evidence indicated that short-term treatment of nonmetastatic breast carcinoma cells with chemotherapeutic agents, such as adriamycin and 5-fluoro-2 deoxyuridine (FUdR), induced a metastatic phenotype in vitro and caused spontaneous lung metastasis within 10 weeks in vivo [12]. In clinical research, circulating tumor cell counts increased in blood samples of patients with breast cancer undergoing neoadjuvant chemotherapy and correlated with distant-metastasis-free survival [13,14]. These studies suggest that chemotherapeutic agents can either select more aggressive cells or enhance the metastatic potential of surviving cells. The molecular mechanism by which chemotherapeutics promote tumor metastasis is still unclear
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