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. 2011 May;178(5):2407-15.
doi: 10.1016/j.ajpath.2011.01.043.

Overexpression of a chromatin remodeling factor, RSF-1/HBXAP, correlates with aggressive oral squamous cell carcinoma

Fu-Min Fang  1 , Chien-Feng Li, Hsuan-Ying Huang, Ming-Tsong Lai, Chih-Mei Chen, I-Wen Chiu, Tian-Li Wang, Fuu-Jen Tsai, Ie-Ming Shih, Jim Jinn-Chyuan Sheu
Affiliations

Overexpression of a chromatin remodeling factor, RSF-1/HBXAP, correlates with aggressive oral squamous cell carcinoma

Fu-Min Fang et al. Am J Pathol. 2011 May.

Abstract

RSF-1, also known as hepatitis B X-antigen associated protein (HBXAP), is a subunit of an ISWI chromatin remodeling complex, remodeling and spacing factor (RSF). Recent studies have provided new evidence that chromatin remodeling participates in the pathogenesis of neoplastic diseases by altering cell cycle regulation and gene expression. In this report, we studied the biological roles of RSF-1 in oral squamous cell carcinoma (OSCC), a highly invasive neoplastic disease. Based on IHC and quantitative real-time PCR, we demonstrated that RSF-1 expression could be detected in the majority of OSCC cases, and the levels were significantly higher in OSCC cells than in their normal counterparts. Moreover, expression levels of RSF-1 significantly correlated with the presence of angiolymphatic invasion, abnormal mitoses, metastasis, tumor recurrence, and advanced stage disease at presentation. Univariate and multivariate analyses showed a significant association of RSF-1 overexpression and worse overall survival in OSCC patients. RSF-1 knockdown remarkably decreased cellular proliferation and induced apoptosis in OSCC cells with high RSF-1 expression levels, but not in those without. Taken together, our results suggest that RSF-1 up-regulation is associated with several clinicopathological features of disease aggressiveness in OSCC patients, and RSF-1 plays an important role in maintaining cellular growth and survival in OSCC.

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Figures

Figure 1
Figure 1
RSF1 gene is overexpressed in oral squamous cell carcinoma (OSCC). A: Representative examples of OSCC were stained with H&E. Based on IHC, RSF-1 immunoreactivity on tumor tissues was scored as 0, +1, +2, +3, or + 4. B: Quantitative real-time PCR (qPCR) analysis indicated higher expression levels of the RSF1 gene in OSCC than in normal epithelial cells. C:RSF1 amplification was frequently found in OSCC tissues analyzed by qPCR. Arrowhead indicates the OSCC sample with highest RSF1 content and gene expression level.
Figure 2
Figure 2
RSF-1 expression correlates with poor clinical outcome in oral squamous cell carcinoma (OSCC). A: Kaplan-Meier survival analysis shows an association between RSF-1 protein expression and shorter overall survival. Patients with immunostaining scores of 0 to + 2 were considered to have low RSF-1 expression; patients with scores of +3 or +4 were considered to have high RSF-1 expression. B: Correlation analysis of RSF-1 expression level and pathological pT status demonstrates that cases with higher pT stages (pT3 and pT4) have higher RSF-1 levels than do lower stage cases (pT1 and pT2).
Figure 3
Figure 3
RSF-1 expression correlates with more tumor aggressiveness in oral squamous cell carcinoma (OSCC). Higher expression levels of RSF-1 were significantly associated with vascular invasion (A) and metastasis (B) to the regional lymph nodes. C: High RSF-1 expressing OSCC samples (scores +3 or +4) showed more frequent atypical mitoses than OSCC samples with low RSF-1 expression (scores 0, +1, or +2). Two pairs of representative H&E and RSF-1 staining tissue sections showed an abnormal number of spindle pole (white arrowhead) and anaphase bridge (black arrowhead), respectively. H&E (hematoxylin and eosion) section with magnification of 40× and RSF-1 IHC (immunohistochemistry) section of 10×.
Figure 4
Figure 4
RSF-1 overexpression is associated with recurrent disease. A: Representative paired primary and recurrent oral squamous cell carcinoma (OSCC) tissues are shown. Stronger nuclear RSF-1 staining was observed in recurrent OSCC. Magnification: ×20 B: Immunohistochemical analyses of 15 paired OSCC tumors from the same patients.
Figure 5
Figure 5
Assessment of RSF1 gene knockdown in RSF-1 expressing oral squamous cell carcinoma (OSCC) cells. A: Western blot analysis revealed the highest expression level of RSF-1 in SAT cells, a moderate level in KON cells, and undetectable levels in SSC4 and CAL27 cells. B: Western blot analysis shows an efficient reduction of RSF-1 protein by RSF-1 specific short-interfering RNA (siRNA). Cells treated with buffer alone (mock) or scramble siRNA were used as the controls. C: Differential growth suppression was found when cells were treated with RSF-1 specific siRNA (blank circles). Cells treated with scramble siRNA were used as the controls (filled circles). DNA synthesis was monitored by (D) Bromodeoxyuridine (BrdU) incorporation and (E) cell death induction was monitored by annexin V staining 4 days after RSF-1-specific siRNA treatment. Cells treated with buffer alone (mock) or scramble siRNA were used as controls. F: Soft agar assay indicates that RSF-1 knockdown leaded to reduction of colony formation in SAT and KON cells, but caused very minor effects on CAL27 cells. Cells treated with scramble served as controls.
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