Clinical significance of SOX9 in human non-small cell lung cancer progression and overall patient survival

Zhou, Chengyu; Ye, Liping; Ye, Shi-Xing; Li, Yan; Zhang, Xinyin; Xu, Xinyu; Gong, Li‐ping

doi:10.1186/1756-9966-31-18

Cited by 64 publications

(54 citation statements)

References 16 publications

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“…Here, we showed that miR145 is an important negative regulator of HNC and that suppressing miR145 expression is crucial for maintaining the stem-like and TICs capacities of HNC. SOX9 is a positive regulator of cancerassociated cellular signaling pathways (10,(34)(35)(36), and its overexpression is associated with poor prognosis and patient survival in breast and lung carcinoma (11,37). We showed that the overexpression of miR145 or the knockdown of SOX9 and ADAM17 suppressed the TICs properties of ALDH þ CD44 þ -HNC cells (Fig.…”

Section: Discussionmentioning

confidence: 92%

miR145 Targets the SOX9/ADAM17 Axis to Inhibit Tumor-Initiating Cells and IL-6–Mediated Paracrine Effects in Head and Neck Cancer

et al. 2013

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ALDH1þ CD44 þ cells are putative tumor-initiating cells (TIC) in head and neck squamous cell carcinomas (HNC). miR-145 regulates tumorigenicity in various cancers but the breadth of its mechanistic contributions and potential therapeutic applications are not completely known. Here, we report that ALDH1 þ CD44 þ -HNC cells express reduced levels of miR145. SPONGE-mediated inhibition of miR-145 (Spg-miR145) was sufficient to drive tumor-initiating characteristics in non-TICs/ALDH1 À CD44-negative HNC cells. Mechanistic analyses identified SOX9 and ADAM17 as two novel miR145 targets relevant to this process. miR-145 expression repressed TICs in HNC in a manner associated with SOX9 interaction with the ADAM17 promoter, thereby activating ADAM17 expression. Notably, the SOX9/ADAM17 axis dominated the TIC-inducing activity of miR-145. Either miR-145 suppression or ADAM17 overexpression in non-TICs/ALDH1À CD44 À -HNC cells increased expression and secretion of interleukin (IL)-6 and soluble-IL-6 receptor (sIL-6R). Conversely, conditioned medium from SpgmiR145-transfected non-TICs/ALDH1 À CD44 À -HNC cells was sufficient to confer tumor-initiating properties in non-TICs/ALDH1À CD44 À -HNC and this effect could be abrogated by an IL-6-neutralizing antibody. We found that curcumin administration increased miR-145 promoter activity, thereby decreasing SOX9/ADAM17 expression and eliminating TICs in HNC cell populations. Delivery of lentivral-miR145 or orally administered curcumin blocked tumor progression in HNC-TICs in murine xenotransplant assays. Finally, immunohistochemical analyses of patient specimens confirmed that an miR-145 low /SOX9 high /ADAM17 high phenotype correlated with poor survival. Collectively, our results show how miR-145 targets the SOX9/ADAM17 axis to regulate TIC properties in HNC, and how altering this pathway may partly explain the anticancer effects of curcumin. By inhibiting IL-6 and sIL-6R as downstream effector cytokines in this pathway, miR-145 seems to suppress a paracrine signaling pathway in the tumor microenvironment that is vital to maintain TICs in HNC. Cancer Res; 73(11); 3425-40. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 92%

miR145 Targets the SOX9/ADAM17 Axis to Inhibit Tumor-Initiating Cells and IL-6–Mediated Paracrine Effects in Head and Neck Cancer

et al. 2013

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“…4H,H9,I,I9). These data demonstrate that Notch activation leads to expression of Sox9, a distal embryonic lung marker that is often expressed in human lung tumors (Jiang et al 2010;Zhou et al 2012).…”

Section: Foxj1mentioning

confidence: 63%

The cell of origin and subtype of K-Ras-induced lung tumors are modified by Notch and Sox2

Xu¹,

Huang²,

Futtner³

et al. 2014

Genes Dev.

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Cell type-specific conditional activation of oncogenic K-Ras is a powerful tool for investigating the cell of origin of adenocarcinomas in the mouse lung. Our previous studies showed that K-Ras activation with a CC10(Scgb1a1)-CreER driver leads to adenocarcinoma in a subset of alveolar type II cells and hyperplasia in the bronchioalveolar duct region. However, no tumors develop in the bronchioles, although recombination occurs throughout this region. To explore underlying mechanisms, we simultaneously modulated either Notch signaling or Sox2 levels in the CC10+ cells along with activation of K-Ras. Inhibition of Notch strongly inhibits adenocarcinoma formation but promotes squamous hyperplasia in the alveoli. In contrast, activation of Notch leads to widespread Sox2+, Sox9+, and CC10+ papillary adenocarcinomas throughout the bronchioles. Chromatin immunoprecipitation demonstrates Sox2 binding to NOTCH1 and NOTCH2 regulatory regions. In transgenic mouse models, overexpression of Sox2 leads to a significant reduction of Notch1 and Notch2 transcripts, while a 50% reduction in Sox2 leads to widespread papillary adenocarcinoma in the bronchioles. Taken together, our data demonstrate that the cell of origin of K-Ras-induced tumors in the lung depends on levels of Sox2 expression affecting Notch signaling. In addition, the subtype of tumors arising from type II cells is determined in part by Notch activation or suppression.

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“…In NSCLC, SOX9 was upregulated at mRNA and protein levels, and the expression levels were associated with the histological stage of NSCLC and patients with a high SOX9 level exhibited a shorter survival rate. Multivariate analysis illustrated that SOX9 upregulation may be an independent prognostic indicator for the survival of patients with NSCLC (39). The overexpression of SOX9 may enhance proliferation, migration and invasion of lung adenocarcinoma cells (40).…”

Section: Discussionmentioning

confidence: 97%

MicroRNA‑216b regulated proliferation and invasion of non‑small cell lung cancer by targeting SOX9

et al. 2018

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Abstract. Micro (mi)RNAs are small, evolutionarily conserved and endogenous noncoding RNA molecules between 19 and 24 nucleotides in length. The potential roles of miRNAs in the carcinogenesis and progression of non-small cell lung cancer (NSCLC) have been studied previously. In the present study, it was revealed that miRNA-216b (miR-216b) expression was lower in NSCLC tissue and cell lines compared with that in adjacent healthy lung tissue samples and the normal bronchial epithelial 16HBE cell line, respectively. The ectopic expression of miR-216b inhibited the proliferation and invasion of NSCLC cells in vitro. SRY-Box 9 (SOX9) was identified as a direct target of miR-216b in NSCLC. In addition, SOX9 small interfering RNA was able to mimic the effects of miR-216b overexpression on cell proliferation and invasion in NSCLC. Therefore, the data reported in the present study demonstrate that miR-216b is an important tumor suppressor in NSCLC. These data may contribute to the understanding of the molecular mechanism underlying the carcinogenesis and progression of NSCLC, and provide novel therapies for patients with NSCLC.

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Clinical significance of SOX9 in human non-small cell lung cancer progression and overall patient survival

Cited by 64 publications

References 16 publications

miR145 Targets the SOX9/ADAM17 Axis to Inhibit Tumor-Initiating Cells and IL-6–Mediated Paracrine Effects in Head and Neck Cancer

miR145 Targets the SOX9/ADAM17 Axis to Inhibit Tumor-Initiating Cells and IL-6–Mediated Paracrine Effects in Head and Neck Cancer

The cell of origin and subtype of K-Ras-induced lung tumors are modified by Notch and Sox2

MicroRNA‑216b regulated proliferation and invasion of non‑small cell lung cancer by targeting SOX9

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