Cytoplasmic expression of SOX9 as a poor prognostic factor for oral squamous cell carcinoma

Abstract

Transcription factor SRY-box 9 (SOX9) is a key regulator of chondrocyte differentiation and sex determination, and it is also involved in the progression of various types of human cancer. However, its putative association with oral squamous cell carcinoma (OSCC) remains elusive. The aim of the present study was to investigate the expression profiles of SOX9 in various oral epithelial lesions, including OSCC. We performed immunohistochemical analysis of SOX9 expression in surgical specimens of OSCC, which simultaneously exhibited different grades of epithelial lesions, and analyzed the correlation between SOX9 expression and several clinicopathological factors. Moreover, we performed immunofluorescent staining, western blot analysis and real-time reverse transcription-polymerase chain reaction to assess SOX9 expression in OSCC HSC-3 (a metastatic cell line) and HSC-4 (a non-metastatic cell line) cell lines. In surgical specimens, SOX9 expression was detected in the nuclei of proliferating cells in areas with epithelial dysplasia and carcinoma in situ, but not in areas with normal epithelia. Nuclear SOX9 expression was observed in most SCC cells. Notably, cytoplasmic SOX9 expression was confirmed only in some SCC cells; however, cytoplasmic SOX9 expression was significantly and positively correlated with poor clinical outcomes. Both protein and mRNA expression of SOX9 were significantly higher in the HSC-3 cell line than that in the HSC-4 line. Notably, however, only HSC-3 cells exhibited cytoplasmic localization of SOX9 expression. Our findings indicate that SOX9 may be involved in the tumorigenesis and progression of OSCC. Furthermore, its cytoplasmic expression represents a potential predictive biomarker for tumor aggressiveness and OSCC prognosis.

Crosstalk between oral squamous cell carcinoma cells and cancer-associated fibroblasts via the TGF-β/SOX9 axis in cancer progression

“…The presence of α-SMA-positive CAFs in the cancer stroma was significantly correlated with the score of the mode of invasion ( p < 0.01), SOX9 positivity in cancer nests ( p < 0.01) and regional recurrence ( p < 0.05). Moreover, as previously shown [18] , high expression of SOX9 was also associated with regional recurrence ( p < 0.05) (data not shown). In the survival analysis, the presence of α-SMA-positive CAFs was significantly correlated with relapse-free survival ( p < 0.01), but was not significantly correlated with disease-specific survival ( p = 0.06) ( Fig.…”

“…Antibodies and reagents [26] , immunofluorescence [18] , TGF-β1 enzyme-linked immunosorbent assay (ELISA), 2D migration assay, MTT cell viability assay, western blot analysis [27] , siRNA transfection, evaluation of the depth of invasion and invasion index in 3D cancer-CAF and cancer-NOF models [28] , xenograft models, immunohistochemistry and evaluation of the localisation of CAFs and SOX9 expression in surgical specimens were available in the supplementary materials and methods.…”

“…Both the high density of macrophages and SOX9 expression are associated with poor prognosis [15] . We recently conducted a histological investigation of SOX9 expression levels in patients with OSCC and demonstrated a correlation between SOX9 expression and poor clinical outcomes [18] . However, the interaction between CAFs and cancer cells through the TGF-β/SOX9 axis has not been thoroughly investigated, especially in OSCC.…”

Structural basis for nuclear import selectivity of pioneer transcription factor SOX2

“…SOX proteins may either maintain or antagonize tumorigenesis 38 – 42 . Cytoplasmic SOX9 correlates with poor clinical cancer outcomes, including both shorter disease-specific survival and relapse-free survival 19 . SOX9 is localized in the cytoplasm of 25–30% invasive ductal carcinomas and lymph node metastases, and its cytoplasmic accumulation significantly correlates with enhanced proliferation in breast tumors 43 .…”

“…This arrangement is conserved across all SOX family members (Fig. 1 ), and mutations within these regions can impair nuclear localization, cause severe developmental disease, and are associated with poor prognosis in cancer 9 , 16 – 19 (see also “Abstract” section).

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