Date Published: July 10, 2017
Publisher: Public Library of Science
Author(s): Pei-Feng Liu, Yu-Chang Hu, Bor-Hwang Kang, Yu-Kai Tseng, Pi-Chuang Wu, Chi-Chuang Liang, Yu-Yi Hou, Ting-Ying Fu, Huei-Han Liou, I-Chien Hsieh, Luo-Ping Ger, Chih-Wen Shu, William B. Coleman.
Apoptosis plays a dual role in cancer development and malignancy. The role of apoptosis-related caspases in cancer remains controversial, particularly in oral tongue squamous cell carcinoma (OTSCC). In this study, we examined the protein levels of cleaved caspase-3, caspase-3, caspase-8, and caspase-9 on tissue microarrays consisting of samples from 246 OTSCC patients by immunohistochemistry. Wilcoxon signed-rank test indicated that the protein levels of cleaved caspase-3, caspase-3, caspase-8, and caspase-9 in tumor tissues were significantly higher compared to those in adjacent normal tissues (all p<0.001). The expression level of caspase-8 in tumors was elevated in patients with lymph node invasion. Moreover, positive expression of cleaved caspase-3 was associated with shorter disease-free survival (DFS) in OTSCC patients with moderate differentiation and lymph node invasion. Combination of either positive cleaved caspase-3 or higher caspase-3 expression or both was associated with poor DFS. Interestingly, stratification analysis showed that co-expression levels of positive cleaved caspase-3 or/and higher caspase-3 were associated with better disease-specific survival in patients with advanced stages of the disease, such as large tumor size and lymph node invasion, whereas it was associated with poor DFS in OTSCC patients with moderate cell differentiation and small tumor size. Taken together, cleaved caspase-3 and caspase-3/8/9 could be biomarkers for tumorigenesis in OTSCC patients. The co-expression level of cleaved caspase-3 and caspase-3 might be a prognostic biomarker for OTSCC patients, particular in those patients with certain tumor stages and cell differentiation status.
Apoptosis, which is type I programmed cell death, is a process with typical morphological characteristics including cell size reduction, cytoplasm condensation, membrane blebbing, chromatin collapse and DNA fragmentation into oligonucleosomal size pieces . Apoptosis is the main mechanism for the elimination of unnecessary cells during development and homeostasis in normal tissue. Thus, dysfunction of the apoptotic system leads to the pathogenesis of a variety of diseases, including cancer [2, 3]. Apoptosis can be triggered to remove cells with damaged DNA to prevent tumorigenesis in precancerous lesions . An impaired apoptotic mechanism allows cancer cells to survive in suspension and promotes tumor angiogenesis and invasiveness, which are crucial steps for cancer metastasis . Tumor cells also evade apoptotic mechanisms to acquire resistance against treatments, and this results in treatment failure [6, 7]. Several promising targeted therapies inhibit anti-apoptotic proteins and induce apoptosis to treat certain types of cancers .
Caspase cascades play crucial roles in apoptosis and are highly associated with cancer development and prognosis. However, the role of expression and activation of various caspases in tumorigenesis remains a double-edged sword. Low expression levels or inactivation of caspases frequently occur in cancer cells and make the cells resistant to microenvironmental stresses and treatments [19, 20]. Conversely, the overexpression of caspases in dying cells may release growth-stimulating signals to allow the non-apoptotic tumor cells to proliferate and survive under stress conditions [16, 17]. To date, little is known about the role of apoptosis-related caspases in OTSCC patients, particularly in a stratification model. In this study, we evaluated the association of the expression of cleaved caspase-3 and caspase-3/8/9 with tumorigenesis and prognosis using a tissue microarray containing 246 OTSCC samples. The findings obtained from the IHC and statistical analyses are as follows. First, the expression levels of cleaved caspase-3 and caspase-3/8/9 in the tumor tissues were significantly higher than those in the adjacent normal tissues. Second, positive expression of cleaved caspase-3 was associated with poor DFS in OTSCC patients, particularly in those with moderate cell differentiation and lymph node invasion. Third, co-expression of either positive cleaved caspase-3 or higher caspase-3 or both were associated with poor DFS in patients with moderately differentiated tumors and small tumor size. However, co-expression of positive cleaved caspase-3 or/and higher caspase-3 was associated with longer DSS in OTSCC patients with advanced disease, such as poor pathological stage, large tumor size and lymph node invasion. Through stratification analysis, these results suggest that the roles of cleaved caspase-3 and caspase-3 in the prognosis of OTSCC might be varied according to the stages of disease. To the best of our knowledge, stratification analysis to determine the relationship between survival curves and expression levels of cleaved caspase-3/caspase-3 in tumor tissues of OTSCC patients has not been previously reported.