Upregulation of SOX9 in Lung Adenocarcinoma and Its Involvement in the Regulation of Cell Growth and Tumorigenicity

Abstract

Purpose: SOX9 is an important transcription factor required for development and has been implicated in several types of cancer. However, SOX9 has never been linked to lung cancer to date. Here, we show that SOX9 expression is upregulated in lung adenocarcinoma and show how it is associated with cancer cell growth.Experimental Design: Data mining with five microarray data sets containing 490 clinical samples, quantitative reverse transcription-PCR validation assay in 57 independent samples, and immunohistochemistry assay with tissue microarrays containing 170 lung tissue cores were used to profile SOX9 mRNA and protein expression. Short interference RNA suppression of SOX9 in cell lines was used to scrutinize functional role(s) of SOX9 and associated molecular mechanisms.Results: SOX9 mRNA and protein were consistently overexpressed in the majority of lung adenocarcinoma. Knockdown of SOX9 in lung adenocarcinoma cell lines resulted in marked decrease of adhesive and anchorage-independent growth in concordance with the upregulation of p21 (CDKN1A) and downregulation of CDK4. In agreement with higher SOX9 expression level in lung adenocarcinoma, the p21 mRNA level was significantly lower in tumors than that in normal tissues, whereas the opposite was true for CDK4, supporting the notion that SOX9 negatively and positively regulated p21 and CDK4, respectively. Finally, whereas SOX9-knockdown cells showed significantly attenuated tumorigenicity in mice, SOX9 transfectants consistently showed markedly stronger tumorigenicity.Conclusions: Our data suggest that SOX9 is a new hallmark of lung adenocarcinoma, in which SOX9 might contribute to gain of tumor growth potential, possibly acting through affecting the expression of cell cycle regulators p21 and CDK4. Clin Cancer Res; 16(17); 4363-73. ©2010 AACR.Lung cancer is currently the most common malignancy and the leading cause of cancer death in the world (1). Clinically, non-small cell lung carcinoma (NSCLC) represents >80% of lung cancers and can be classified into adenocarcinoma (ADC), squamous cell carcinoma (SQC), and large cell carcinoma. ADC and SQC constitutes two major subtypes of NSCLC, and there is a trend that incidence of ADC is increasing worldwide, particularly in women (2, 3). In addition, ADC is the most common histologic types of lung cancers arising in never and former smokers (4, 5). The 5-year survival rate for all stages of NSCLC patients is only ∼15%, majorly due to diagnosis at late stage when tumor has progressed and become inoperable. Given the life-threatening nature of lung cancers, it is important to identify biomarkers for their early detection and prognosis, and to obtain a better understanding of the underlying mechanisms with respect to the functional roles of the molecules involved in the development and advances of the cancer. Although many markers from gene expression profiling analysis of lung cancers have Authors' Affiliations:

In�vitro study on the role of SOX9 in trastuzumab resistance of adenocarcinoma of the esophagogastric junction

“…In the present study, it was revealed that SOX9 knockdown led to suppressed cell proliferation and increased cell apoptosis, indicating that SOX9 is a tumor promoter in AEG. This finding is consistent with the role of SOX9 in other types of tumor (20)(21)(22). It has previously been reported that SOX9 mediates the effect of certain antitumor drugs; SOX9 expression was markedly inhibited in mice tumors by combination treatment with ABT-263 and 5-FU (24).…”

“…The importance of SOX9 in tumorigenesis has been identified, and the dysregulation of SOX9 has been implicated in several cancers, including prostate cancer, lung adenocarcinoma and gastric carcinoma (20)(21)(22). Overexpression of SOX9 has been demonstrated to increase tumor growth, invasion and angiogenesis (14,23).…”

SOX9 accelerates ESC differentiation to three germ layer lineages by repressing SOX2 expression through P21 (WAF1/CIP1)

“…The paradigm identified here in ESC differentiation may apply to other stem cells and progenitors, and also to cancer cells. SOX9 is highly expressed in cancers of the skin, prostate, lung, colon and brain (Kordes and Hagel, 2006;Vidal et al, 2008;Wang et al, 2008;Jiang et al, 2010;Matheu et al, 2012). However, whether SOX9 has an effect on tumor growth is still controversial.…”

“…However, whether SOX9 has an effect on tumor growth is still controversial. SOX9 has shown several pro-oncogenic properties, including the ability to promote proliferation, to inhibit senescence and to collaborate with other oncogenes in neoplastic transformation (Wang et al, 2008;Jiang et al, 2010;Matheu et al, 2012). But some reports demonstrated that overexpression of SOX9 in human melanoma or human endometrial carcinoma, as well as in chondrocytes, inhibited cell proliferation through P21 expression in cooperation with p53 (Panda et al, 2001;Passeron et al, 2009;Saegusa et al, 2012).…”

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“…Furthermore, strong SOX9 expression is an independent indicator for an adverse prognosis in colorectal cancer [39]. Jiang demonstrated the upregulation of SOX9 expression in lung adenocarcinoma and its direct effect on cell growth through its effect on the expression of cell cycle regulators [40]. Likewise, Huang demonstrated the role of SOX9 in the initiation of prostate cancer [41].…”