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

Department of Biochemistry and Molecular Biology, School of medicine, ShenZhen University, Shen Zhen, China.
Journal of Experimental & Clinical Cancer Research (Impact Factor: 4.43). 03/2012; 31(1):18. DOI: 10.1186/1756-9966-31-18
Source: PubMed


Sex determining region Y (SRY)-related high mobility groupbox 9 (SOX9) is an important transcription factor required for development, which regulates the expression of target genes in the associated pathway. The aim of this study was to describe the expression of SOX9 in human non-small cell lung cancer (NSCLC) and to investigate the association between SOX9 expression and progression of NSCLC.
SOX9 protein and mRNA expression in normal human pneumonocytes, lung cancer cell lines, and eight pairs of matched lung cancer tissues and their adjacent normal lung tissues were detected by Western blotting and real-time reverse transcription-polymerase chain reaction (RT-PCR). Immunohistochemistry was used to determine SOX9 protein expression in 142 cases of histologically characterized NSCLC. Statistical analyses were applied to test for prognostic and diagnostic associations.
SOX9 in lung cancer cell lines was upregulated at both mRNA and protein levels, and SOX9 mRNA and protein were also elevated in NSCLC tissues compared with levels in corresponding adjacent non-cancerous lung tissues. Immunohistochemical analysis demonstrated a high expression of SOX9 in 74/142 (52.1%) paraffin-embedded archival lung cancer biopsies. Statistical analysis indicated that upregulation of SOX9 was significantly correlated with the histological stage of NSCLC (P=0.017) and that patients with a high SOX9 level exhibited a shorter survival time (P<0.001). Multivariate analysis illustrated that SOX9 upregulation might be an independent prognostic indicator for the survival of patients with NSCLC.
This work shows that SOX9 may serve as a novel and prognostic marker for NSCLC, and play a role during the development and progression of the disease.

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    • "However, lack of p38 signalling specifically promotes anchoring-independent growth in soft agar (a hallmark of cellular transformation), of oncogenic but not of WT cells (Fig. 2C). Correlating to the transforming capacity, absence of p38 activity induces an upregulation of the expression of the stem and lung cancer marker Sox9 [9], [10] in K-RasG12 cells (Fig. 2D and Fig. S1F) supporting its potential as a therapeutic target. "
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    ABSTRACT: Lung cancer is the cause of most cancer-related deaths in the Western world. Non-small cell lung cancer accounts for almost 80% of all lung cancers, and 50% of this type are adenocarcinomas. The cellular and molecular origin of this type of lung cancer remains elusive and the mechanisms are poorly known. It is known that K-Ras mutations appear in 25-30% of lung adenocarcinomas and it is the best known single mutation that can be related to lung cancers. Recently, it has been suggested that a putative population of mouse bronchioalveolar stem cells could be considered as the cell of origin of adenocarcinomas. These cells are expanded in the early stages of lung tumorigenesis. We have isolated a population of mouse bronchioalveolar stem cells and induced their transformation by oncogenic K-RasG12. Different approaches have shown that an intracellular network linking the p38α MAPK and the PI3K-Pdk1 pathways is involved in regulating the survival and malignant progression of the transformed cells. Absence of p38α catalytic activity leads to further Pdk1 activation (independent of Akt and Erk activity), enhancing the survival and proliferation of the more malignant lung cancer cells. This specifically selects high Sca-1/Sox9 cells that harbour a stronger colonizing potential, as they maintain their capacity to produce secondary tumors after serial transplantations.
    PLoS ONE 11/2013; 8(11):e78911. DOI:10.1371/journal.pone.0078911 · 3.23 Impact Factor
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    • "Since it is well recognized that genes and pathways critical for development may also play important roles in cancer development and progression, it is not surprising that SOX9 is involved in cancers. Zhou et al. [9] reported that the elevated expression of SOX9 may be related with the progression of gastric carcinoma; Chakravarty et al. [10] demonstrated that cytoplasmic SOX9 may serve as a valuable prognostic marker for invasive ductal carcinomas and metastatic breast cancer, and its significant correlation with breast tumor cell proliferation implied that SOX9 may directly contribute to the poor clinical outcomes associated with invasive breast cancer; Vidal et al. [11] found that SOX9 expression was a general feature of basal cell carcinoma and adnexal skin neoplasms; Lü et al. [12] suggested that SOX9 expression may be upregulated in colorectal cancer and strong SOX9 expression may be an independent adverse prognosticator in this cancer; Huang et al. [13] indicated that Sox9 may be required for prostate development and prostate cancer initiation; Zhou et al. [14] reported that SOX9 upregulation may be an independent prognostic indicator for the survival of patients with non-small cell lung cancer; Tanaka et al. [15] also found that SOX9 might contribute to carcinogenesis in pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm. In contrast, Passeron et al. [17] analyzed SOX9 expression in melanoma and discovered that SOX9 expression gradually decreased according to disease progress from normal skin to nevi, primary melanoma, and metastatic melanoma. "
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    ABSTRACT: SOX9 plays an important role in bone formation and tumorigenesis. However, its involvement in osteosarcoma is still unclear. The aim of this study was to investigate the expression pattern and the clinical significance of SOX9 in human osteosarcoma. SOX9 mRNA and protein expression levels were detected by RT-PCR and Western blot assays, respectively, using 30 pairs of osteosarcoma and noncancerous bone tissues. Then, immunohistochemistry was performed to analyze the association of SOX9 expression in 166 osteosarcoma tissues with clinicopathological factors or survival of patients. SOX9 expression at mRNA and protein levels were both significantly higher in osteosarcoma tissues than those in corresponding noncancerous bone tissues (both P < 0.001). Immunohistochemical staining indicated that SOX9 localized to the nucleus and high SOX9 expression was observed in 120 of 166 (72.3%) osteosarcoma specimens. In addition, high SOX9 expression was more frequently occurred in osteosarcoma tissues with advanced clinical stage (P = 0.02), positive distant metastasis (P = 0.008) and poor response to chemotherapy (P = 0.02). Osteosarcoma patients with high SOX9 expression had shorter overall survival and disease-free survival (both P < 0.001). Furthermore, the multivariate analysis confirmed that upregulation of SOX9 was an independent and significant prognostic factor to predict poor overall survival and disease-free survival (both P = 0.006). Our data show for the first time that SOX9 is upregulated in aggressive osteosarcoma tissues indicating that SOX9 may participate in the osteosarcoma progression. More importantly, SOX9 status is a useful prognostic factor for predicting the prognosis of osteosarcoma, suggesting that SOX9 may contribute to the optimization of clinical treatments for osteosarcoma patients.Virtual slides: The virtual slides for this article can be found here:
    Diagnostic Pathology 11/2013; 8(1):183. DOI:10.1186/1746-1596-8-183 · 2.60 Impact Factor
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    ABSTRACT: Introduction: It has been more that 20 years since the first SOX genes were discovered. Twenty SOX genes have now been identified in mammals and classified into groups with respect to protein identity. SOX family genes code for transcription factors that either activate or repress lineage-specific genes during embryonic development. Furthermore, SOX genes are altered in human genetic syndromes and malignancies, highlighting their involvement in development. Areas covered: This paper reviews the role of SOX genes in embryonic development and human diseases, and describe their involvement in human cancers and possible use in cancer therapeutics. Expert opinion: Since most SOX genes behave as oncogenes in many human cancers, their targeting has great therapeutic potential. However, novel specific therapies such as those recently developed against growth factor receptors based on monoclonal antibodies, small inhibitors and even small interfering RNA strategies are difficult to implement for transcriptional factors. Novel strategies are being developed to overcome some of these obstacles. Alternative approaches could indirectly tackle altered SOX genes by exploiting the related molecular networks.
    Expert Opinion on Therapeutic Targets 07/2012; 16(9):903-19. DOI:10.1517/14728222.2012.709239 · 5.14 Impact Factor
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