Bmi1 expression in oral lichen planus and the risk of progression to oral squamous cell carcinoma

Oral lichen planus (OLP) is a potentially malignant disorder associated with an increased risk of progression to oral squamous cell carcinoma (OSCC). The objective of this study was to determine protein expression of cancer stem cell factor Bmi1 in a longitudinal series of patients with OLP and evaluate the correlation between Bmi1 expression and the risk of progression to OSCC. In a retrospective study, Bmi1 expression was determined using immunohistochemistry in samples from 96 patients with OLP who received a mean follow-up of 54 months, including patients who did not progress to OSCC (n = 87) and patients who had progressed to OSCC (n = 9). Analysis of 10 cases of normal oral mucosa and 6 cases of postmalignant OSCC form previously diagnosed OLP was also performed. The results showed that Bmi1 expression was observed in 32 (36.8%) of 87 cases of nonprogressing OLP and in 8 (88.9%) of 9 cases of progressing OLP. Bmi1 was not expressed in normal oral mucosa, but it was positively expressed in the 6 (100%) cases of OSCC. Multivariate analysis revealed that the risk of malignant progression in the patients with Bmi1-positive expression was significantly higher than those with Bmi1 negativity (odds ratio, 20.75; 95% confidence interval, 2.21-194.57; P = .008). Collectively, Bmi1 expression was significantly associated with malignant transformation in a large series of patients with OLP who received a longitudinal observation. Our findings suggested that Bmi1 may serve as a useful marker for the identification of a high risk of malignant progression of OLP.     

Immunohistochemical expression of p16 protein in oral squamous cell carcinoma and lichen planus

Epithelial carcinogenesis is a multistep process. Specific genetic events lead to malignant transformation of oral epithelium. Oral squamous cell carcinoma (OSCC) may be preceded by potentially malignant lesions such as oral lichen planus (OLP). The p16 protein functions as a negative regulator of the cell cycle progression. Altered pattern of p16 serves as a biomarker for oral mucosal dysplasia and malignant growth. The purpose of this study was to evaluate p16 expression in OSCC and OLP to determine whether it can be a useful marker for early detection of carcinogenesis. We examined p16 expression in 45 OSCCs (15 grade I, 15 grade II, and 15 grade III), 15 OLPs without dysplasia, and 8 normal mucosal specimens with immunohistochemistry. p16 was interpreted as positive if more than 70% of tumor cells showed brown nuclear and cytoplasmic staining. All of the OSCC and control group samples showed negative immunoreactivity, whereas 26.7% of OLP samples were positive for p16. Our findings suggest that p16 expression could not be used as a helpful marker for detection of development toward malignancy in OLP samples.     

Aldehyde dehydrogenase 1 expression correlated with malignant potential of oral lichen planus

Oral lichen planus (OLP) is a potentially malignant disorder associated with an increased risk of oral squamous cell carcinoma (OSCC). The objective of this study was to determine protein expression of cancer stem cell marker aldehyde dehydrogenase 1 (ALDH1) in a series of patients with OLP and evaluate the correlation between ALDH1 expression and the risk of progression to OSCC. In a retrospective study, ALDH1 expression was determined using immunohistochemistry in samples from 101 patients with OLP who received a mean follow-up of 5 years, including 89 patients with untransformed OLP that did not develop into OSCC and 12 patients with malignant transformed OLP that had developed into OSCC. Analysis of 10 cases of normal oral mucosa and 6 cases of postmalignant OSCC form previously diagnosed OLP was also performed. The results showed that ALDH1 expression was observed in 27 (30.3%) of 89 cases of untransformed OLP and in 8 (66.7%) of 12 cases of transformed OLP (P = .021). Aldehyde dehydrogenase 1 was not expressed in normal oral mucosa, but it overexpressed in the 6 cases (100%) of OSCC. Multivariate analysis revealed that ALDH1 expression was significantly associated with a 6.71-fold (95% confidence interval, 1.64-27.42; P = .008) increased risk of malignant transformation. Collectively, ALDH1 expression was significantly associated with malignant transformation in a large series of patients with OLP. Our findings suggested that ALDH1 expression may identify a subgroup of a higher risk of malignant transformation of OLP.     

In oral squamous cell carcinoma, high FAK expression is correlated with low P53 expression

Focal adhesion kinase (FAK) and p53 have been associated with metastatic activity and a poor prognosis in oral squamous cell carcinoma (OSCC). Recently, a feedback mechanism in which FAK regulates p53 has been proposed. The present study aims to determine the role of p53 in FAK regulation in these tumors. FAK and p53 expression was examined by immunohistochemistry in normal oral mucosa and in 67 oral squamous cell carcinomas. p16(INK4a) was also studied in view of its association with human papillomavirus infection. The association between FAK and p53 was subsequently analyzed. FAK expression in OSCCs was heterogeneous: 22 (33?%) cases showed weak expression, 16 (24?%) showed moderate expression, and 22 (33?%) cases showed high expression. Regarding p53, 31 of 67 (46?%) available tumor specimens showed negative staining, and 36 of 67 (54?%) showed positive nuclear staining for p53. FAK expression was inversely correlated with p53 expression (Fisher's exact test, p?=?0.005). There was no association between p16(INK4a) and p53 or FAK expression. In conclusion, our results support the hypothesis that FAK activity might be involved in the down-regulation of p53 expression in OSCC.     

Comparative analysis of the expression of proliferating cell nuclear antigen, p53, bax, and bcl-2 in oral lichen planus and oral squamous cell carcinoma

Several epidemiologic studies have shown the malignant transformation potential of oral lichen planus; however, this potential is subject of much controversy. To evaluate the expression of proteins related to the cell proliferation and apoptosis processes in oral lichen planus, we compared oral lichen planus with oral squamous cell carcinoma. Twenty-four cases of each lesion were submitted according to streptavidin-biotin technique to evaluate the immunohistochemical expression of proliferating cell nuclear antigen, p53, bax, and bcl-2 proteins. χ² test showed no statistically significant differences between the expression of p53, bax, and bcl-2 in oral lichen planus and oral squamous cell carcinoma (P > .05). However, the expression of proliferating cell nuclear antigen was significantly lower in oral lichen planus than in oral squamous cell carcinoma (P < .05). No statistically significant differences between the expression of p53, bax, and bcl-2 in oral lichen planus and oral squamous cell carcinoma were observed, which may be an evidence of the potential of malignant transformation of oral lichen planus.     

High expression of TROP2 is correlated with poor prognosis of oral squamous cell carcinoma

Human trophoblastic cell-surface antigen 2 (TROP2) is a cell surface glycoprotein that exhibits high expression in various carcinomas but low or no expression in normal tissues. High TROP2 expression plays an important role in promoting tumor development and aggressiveness, which is correlated with reduced patient survival. However, there are few studies regarding TROP2 in relation to both oral squamous cell carcinoma (OSCC) and oral potentially malignant lesions. The expression of TROP2 protein and mRNA was investigated in OSCC tissues, oral potentially malignant lesion tissues, and normal oral tissues using immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). The association between TROP2 expression and clinicopathological characteristics of OSCC was also analyzed, and the prognostic value of TROP2 was evaluated. The expression of TROP2 protein and mRNA were both higher in OSCC tissues than in oral potentially malignant lesion tissues or normal oral tissues. Positive TROP2 expression was related to differentiation, lymph node metastases, TNM stage, perineural infiltration, and vascular invasion. Poor overall survival was associated with high TROP2 expression and other factors associated with poor overall survival including poor differentiation, lymph node metastasis, TNM stage, vascular invasion, and perineural invasion in univariate analyses. TROP2 expression as well as TNM stage and vascular invasion were independent prognostic factors associated with the overall survival of OSCC patients in multivariate analyses. In summary, High TROP2 expression is associated with poor overall survival and serves as an independent prognostic factor in OSCC. The results suggest that TROP2 expression could be an effective prognostic biomarker for OSCC.     

Cytotoxic molecule expression and epithelial cell apoptosis in oral and cutaneous lichen planus

We evaluated the expression of T cell-restricted intracellular antigen (Tia-1), granzyme B, and perforin by lymphocytes and the degree of epithelial apoptosis in oral and cutaneous lichen planus (LP) in 51 untreated cases, including 27 oral LP (OLP) and 24 cutaneous LP (CLP) cases. The number of total dermal-positive lymphocytes in OLP and CLP was similar, indicating similar activity of the inflammatory process. Intraepithelial Tia-1-positive, perforin-positive, and granzyme B-positive lymphoid cells were more numerous in OLP than in CLP (P < .05). The epithelial cell apoptotic index (AI) was increased significantly in OLP (P < .05), particularly in erosive-atrophic variants. A linear correlation between AI and the mean +/- SEM number of intraepithelial and dermal perforin+ cells (6.85 +/- 2.44 and 27.48 +/- 10.19, respectively), per 10 high-power fields for OLP and for CLP (1.17 +/- 0.88 and 10.42 +/- 5.74, respectively), was found (intraepithelial, r = 0.50; dermal, r = 0.51; P < .01). These data suggest a pivotal role for perforin in triggering epithelial cell apoptosis. The differences of infiltrating cytotoxic cells and related AI observed in OLP and CLP are in keeping with the clinical behaviors that distinguish these LP variants.     

Decreased expression of TFPI-2 correlated with increased expression of CD133 in cholangiocarcinoma

Background: Recent findings suggest decreasing TFPI-2 expression plays a significant role in inhibiting cell migration and tumor invasion. The clinicopathological significance of the expression of TFPI-2 and its possible correlation with the expression of CD133 in cholangiocarcinoma remains to be solved. Methods: We investigated if TFPI-2 was involved in the clinicopathological significance of cholangiocarcinoma. An immunohistochemical method was used to detect 218 cases of cholangiocarcinoma, 30 para-neoplastic and 20 normal bile ducts for their expression status of TFPI-2 and CD133, and then the results were analyzed with the patient’s age, sex, tumor site and the histological grade, clinical stage as well as overall mean survival time. Results: Compared with the para-neoplastic and normal cholangiocytes, the expression of TFPI-2 was obviously decreased while the expression of CD133 in carcinoma cells was increased. Carcinomas with low expression of TFPI-2 were significantly corresponding to the tumor site (P = 0.006), size (P = 0.005), histological grade (P = 0.0001) and clinical stage (P = 0.0001), but not to the age (P = 0.066) and sex (P = 0.411), respectively. By Kaplan-Meier survival analysis, the low expression of TFPI-2 was significantly correlative with the overall survival time (P = 0.0001). Further, the expression of TFPI-2 was found inversely correlative with the expression of CD133 (g = -0.3876, P < 0.0001). Conclusions: Our finding suggests that the decreased expression of TFPI-2 may play an important role in the carcinogenesis and progression, and may become a new adjunct marker in the diagnosis and prognosis in cholangiocarcinoma. The expression of TFPI-2 may be inversely correlative with the expression of CD133.     

TRIP13 upregulation is correlated with poor prognosis and tumor progression in esophageal squamous cell carcinoma

Thyroid receptor-interacting protein 13 (TRIP13), a member of the AAA + ATPase super-family, has been proved to be upregulated and identified as a prognostic factor in multiple human cancers, However, the role of TRIP13 in esophageal squamous cell carcinoma (ESCC) and its clinic relevance remains unclear. In the present study, we performed database-mining and detected TRIP13 expression in 158 tissue samples (79 ESCC tissue and 79 matched adjunct non-cancerous tissues). We further investigated the correlation between TRIP13 expression and clinicopathological features and overall survival. Univariate and multivariate Cox regression analyses were applied to evaluate the potential prognostic value of TRIP13 in ESCC patients. In addition, the mechanisms involved in TRIP13 tumor-promoting effect was investigated. Data showed that TRIP13 expression was significantly increased in ESCC tissues, compared with the matched adjunct non-cancerous tissues. Expression of TRIP13 is significantly correlated with T status (P = 0.027), lymphatic metastasis (P = 0.017), and clinical stages of ESCC (P = 0.009). Kaplan-Meier analyses showed that patients with high TRIP13 expression had poor overall survival (P = 0.0022). Multivariate analysis indicated that TRIP13 expression might be an independent prognostic factor in ESCC patients (HR, 1.778, 95% confidence interval = 0.959–3.296, P = 0.028). Furthermore, downregulating TRIP13 in EC109 cell significantly attenuated the cell proliferation and progression, possibly by β-catenin regulated EMT pathway.Conclusions: Our study demonstrated that TRIP13 might be a tumor promoting factor in ESCC and a promising prognostic indicator for ESCC patient.     

Upregulated CD44v9 expression inhibits the invasion of oral squamous cell carcinoma cells.

OBJECTIVES: CD44 is one of the cell surface molecules that play an important role in cancer metastasis. In oral squamous cell carcinoma (OSCC), the downregulation of CD44v9 has been shown to be associated with tumor metastasis. We found that treatment with an anti-CD44v9 antibody enhanced the invasive potential of OSCC cell lines. Based on previous studies and our results, reduced expression of CD44v9 may be correlated with an increased invasive potential, i.e. the overexpression of CD44v9 may inhibit the invasive activity of OSCC cells. METHODS: To study this correlation, we transfected the CD44v9 gene into HSC-4 cells with low CD44v9 expression and examined their invasive potential using the cell culture invasion assay and a three-dimensional culture invasion assay. RESULTS: Overexpression of CD44v9 resulted in a downregulation of the invasive potential of HSC-4 cells. Moreover, CD44v9-transfected cells did not invade reorganized stroma, while parent HSC-4 cells exhibited diffuse invasion into reorganized stroma by the three-dimensional culture invasion assay. CONCLUSIONS: Overall, these findings suggest that the inhibition of the invasive potential by upregulation of CD44v9 expression may be due to enhanced cell-cell adhesion. In our opinion, the upregulation of CD44v9 may be a target for future cancer treatment.     

Destruction of basement membrane and cell infiltrates in oral lichen planus

Immunohistochemical staining analysis of oral lichen planus (OLP) using monoclonal antibodies (MoAbs) against the components of basement membrane (BM) and infiltrated cells was performed in 27 cases. Integrity of lining epithelial BM was more strictly elucidated by staining for laminin and type IV collagen than by fibronectin. Staining patterns of laminin were similar to type IV collagen. In the cases examined, continuity of BM was proven by laminin staining in 10 cases, partially destructive BM was seen in 9 cases and complete destruction of BM in 8 cases. Dividing OLP into 20 symptomatic (ulcerative/erosive) and 7 asymptomatic (non-ulcerative/-erosive) cases, intact BM could be observed in only 5 cases of the symptomatic group, while 5 cases of the other group possessed undamaged BM. The difference between the two groups was significant. Stromal and epidermal cell infiltrates, which were mainly composed of T cell subsets with accompanying Leu-M5 and 6-positive cells, were correlated with the condition of BM. Stromal Leu-M5+ and Leu-6+ cell infiltrates were clearly more dominant in laminin-negative (BM-destructed) cases than infiltrates in BM-intact cases. This relation was also found in epidermal infiltrates with the same manner of Leu-4 infiltration. From the above, it seems that the integrity of BM is concerned with cell infiltrates and clinical manifestations of OLP.     

Interstitial collagenase gene expression in oral squamous cell carcinoma.

In this study, in situ hybridization techniques were used to determine the location of interstitial collagenase and tissue inhibitor of metalloproteinase (TIMP) gene expression in samples from 11 squamous cell carcinomas of the head and neck (particularly the oral cavity) and from non-neoplastic mucosa of the same region. Ten of the 11 carcinomas examined showed abundant levels of collagenase gene expression in stromal fibroblasts within connective tissues immediately adjacent to tumor masses. Lower levels were detected in basaloid tumor cells located at the periphery of several tumor masses. Interstitial collagenase expression was consistently low in all normal, hyperplastic, and dysplastic epithelial sections. TIMP gene expression was negligible in all tissues examined. These results support the view that stromal interstitial collagenase production may play a key role in assisting invasiveness of squamous cell carcinoma of the head and neck.     

Mesenchymal stem cell transplantation: a potential therapy for oral lichen planus

Oral lichen planus is a type of T cell-mediated autoimmune disease. Satisfactory therapy results are not usually achieved with conventional treatment; however, a new therapy employing T cell immune modulation may treat this disease. Mesenchymal stem cells are multipotent nonhematopoietic progenitor cells that are capable of self-renewal and differentiation into various cell types, including osteocytes and adipocytes. Thus, mesenchymal stem cells are regarded as a promising cell population for tissue regeneration in the clinic. In the past several years, there has been a dramatic improvement in the understanding of immunosuppressive properties of mesenchymal stem cells on various immune cell types. We propose that mesenchymal stem cells can be utilized to treat oral lichen planus patients via systemic infusion or local application.