Dataset Information

Sox9 mediates Notch1-induced mesenchymal features in lung adenocarcinoma.

ABSTRACT: Sox9 has gained increasing importance both functionally and as a prognostic factor in cancer. We demonstrate a functional role for Sox9 in inducing a mesenchymal phenotype in lung ADC. We show that Sox9 mRNA and protein are overexpressed in lung ADC, particularly those with KRAS mutations. Sox9 expression correlated with the Notch target gene Hes1, and numerous other Notch pathway components. We observed that Sox9 is a potent inducer of lung cancer cell motility and invasion, and a negative regulator of E-cadherin, a key protein that is lost during epithelial-mesenchymal transition (EMT). Moreover, we show that Notch1 signaling directly regulates Sox9 expression through a SOX9 promoter binding site, independently of the TGF-? pathway, and that Sox9 participates in Notch-1 induced cell motility, cell invasion, and loss of E-cadherin expression. Together, the results identify a new functional role for a Notch1-Sox9 signaling axis in lung ADC that may explain the correlation of Sox9 with tumor progression, higher tumor grade, and poor lung cancer survival. In addition to Notch and TGF-?, Sox9 also acts downstream of NF-?B, BMP, EGFR, and Wnt/?-catenin signaling. Thus, Sox9 could potentially act as a hub to mediate cross-talk among key oncogenic pathways in lung ADC. Targeting Sox9 expression or transcriptional activity could potentially reduce resistance to targeted therapy for lung ADC caused by pathway redundancy.

SUBMITTER: Capaccione KM

PROVIDER: S-EPMC4116509 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Sox9 mediates Notch1-induced mesenchymal features in lung adenocarcinoma.

Capaccione Kathleen M KM Hong Xuehui X Morgan Katherine M KM Liu Wenyu W Bishop J Michael JM Liu LianXin L Markert Elke E Deen Malik M Minerowicz Christine C Bertino Joseph R JR Allen Thaddeus T Pine Sharon R SR

Oncotarget 20140601 11

Sox9 has gained increasing importance both functionally and as a prognostic factor in cancer. We demonstrate a functional role for Sox9 in inducing a mesenchymal phenotype in lung ADC. We show that Sox9 mRNA and protein are overexpressed in lung ADC, particularly those with KRAS mutations. Sox9 expression correlated with the Notch target gene Hes1, and numerous other Notch pathway components. We observed that Sox9 is a potent inducer of lung cancer cell motility and invasion, and a negative regu ...[more]

PMID: 25004243

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Project description:Simple Summary Chemotherapeutic 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. Abstract 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.

Dataset Information

Sox9 mediates Notch1-induced mesenchymal features in lung adenocarcinoma.

Publications

Sox9 mediates Notch1-induced mesenchymal features in lung adenocarcinoma.

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