Lung cancer is the leading cause of cancer-related death in many countries in the world. Among all subtypes of lung cancer, non-small cell lung carcinoma (NSCLC) is the most frequent one, which accounts for greater than 80% of lung cancers.The prognosis of NSCLC patients is poor, with the 5-year survival rate of only about 18%, and the high mortality of NSCLC is thought to be attributed to difficulties in early diagnosis and the lack of effective therapeutic methods in general. NSCLC can be further classified into three histological subtypes, i.e., squamous cell carcinoma (SQC), adenocarcinoma (ADC) and large cell carcinoma (LCC). Among these subtypes, SQC and ADC are the major ones, which together represent ∼70% of NSCLC. SQC was once the most common subtype of NSCLC during the past century. However, it was noted later that proportion of SQC relative to ADC declined gradually, most probably owing to change in smoking behavior and improved diagnostic methods. Today, ADC is the most common subtype in many countries, while SQC is estimated to account for 20–25% of NSCLCs.

Compared with ADC of the lung, in which many driver mutations have been identified and targeted therapies are applicable to a good proportion of patients especially in the Far Eastern countries, neoplasms of SQC of the lung were once regarded as tumors without readily targetable genetic abnormalities. However, recent studies have identified new lung SQC-associated genetic changes, including the amplification and overexpression of SOX2. SOX2 is located on chromosome 3q26, a region amplified in about 20% of lung SQC. At a much higher rate than gene amplification, overexpression of SOX2 mRNA was observed in about 90% of the lung SQC, indicating that SOX2 might play oncogenic role(s) in the tumorigenesis of lung SQC, which is supported by studies reporting that SOX2 is a lineage-survival oncogene of SQC of the lung.

As SOX2 functions upstream of the hierarchy of gene expression network, it is likely that its aberrant expression in lung epithelia could cause profound change in a wide variety of molecular pathways, which may contribute to growth and survival of the lung SQC cells. Although the oncogenic role of SOX2 in lung SQC has been identified, there is still a paucity in the understanding of the mechanisms regarding how SOX2-mediated signaling network affects the formation or progression of lung SQC cells.

In an initiative, using SOX2-abundant lung SQC cell lines, Wen-Tsen Fang et al. screened for genes whose expression was not only affected by silencing of SOX2 but can also account for the inhibition of cell growth upon SOX2 silencing. Among the other candidate genes, they found that BMP4, a member of the TGF-β superfamily genes, was significantly affected by silencing SOX2. As genes of TGF-β family are well known for their involvement in the regulation of cell proliferation and differentiation, they postulated that BMP4 is a plausible target of SOX2. In their study, several lines of evidence from in vitro and in vivo observation were provided showing that BMP4 expression may be transcriptionally suppressed by SOX2 to promote growth of lung SQC cells.

Reference:

Downregulation of a putative tumor suppressor BMP4 by SOX2 promotes growth of lung squamous cell carcinoma. Cancer Cell Biology.2014;135:809-819