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Abstract
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.
Highlights
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 [1]
To compare the expression levels of cleaved caspase-3 and caspase-3/8/9 in oral tongue squamous cell carcinoma (OTSCC) patients, the tumor tissues and tumor adjacent normal tissues were stained by immunohistochemistry for the determination of protein levels
Since caspase-3 can be cleaved to give rise to the active form, we further examined if the combined expression pattern of cleaved caspase-3 and caspase-3 is associated with the prognosis of OTSCC patients
Summary
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 [1]. Apoptosis is the main mechanism for the elimination of unnecessary cells during development and homeostasis in normal tissue. 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 [4]. An impaired apoptotic mechanism allows cancer cells to survive in suspension and promotes tumor angiogenesis and invasiveness, which are crucial steps for cancer metastasis [5]. Tumor cells 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 [8]
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