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Regulation Of Prostate Cancer Progression By Galectin-3

October 12, 2017

UroToday - Prostate cancer has posed a major public health problem in the United States and worldwide. There is a continuous search for better diagnostic markers and therapeutic targets for this disease. Galectin-3 is a β-galactoside-binding protein, which binds to the carbohydrate portion of cell surface glycoproteins or glycolipids (1, 2). It has been implicated in a variety of biological functions including cell proliferation, apoptosis, angiogenesis, tumor progression and metastasis.

A growing body of literature describes the correlation of galectin-3 with neoplastic progression. In human prostate cancer, galectin-3 expression was reported to be down-regulated with progressive stages (3-6), while in many other cancers like thyroid, gastric carcinoma, and squamous cell carcinoma of the head and neck, galectin-3 expression was up-regulated with increased malignant phenotype (7-9). Recently, in vivo cleavage of galectin-3 was reported in breast cancer using two specific antibodies: a monoclonal antibody, which recognizes intact galectin-3 and a polyclonal antibody, which recognizes both intact and cleaved galectin-3 (10) . We questioned whether cleavage of galectin-3 might be also a part of prostate cancer progression and could be detected in biopsies. In our study, we evaluated the role of galectin-3 during the progression of human prostate cancer using two approaches:

1) staining human prostate cancer tissues with differential antibodies,

2) investigating the association of galectin-3 with biological behavior of prostate cancer PC3 cells by silencing its expression.

Human prostate cancer tissue array was analyzed by immunohistochemistry using two differential anti-galectin-3 antibodies. We found that no cleavage of galectin-3 occurred in normal or PIN tissue samples, however, in Gleason 3 and 4 cancer tissues, a significantly higher percentage of positive samples and more galectin-3 positive cells in the same section using polyclonal antibody compared to the monoclonal antibody indicate the cleavage of galectin-3. Our data demonstrated that galectin-3 is cleaved during the malignant transformation of human prostate cancer, which suggested that cleavage of galectin-3, not just the presence of intact galectin-3, could be used as the maker for diagnosis of prostate cancer. To date, the actual biological functions of galectin-3 in prostate cancer have not been well described. Our study showed that silencing of galectin-3 using siRNA in PC3 cells contributed to reduced cell migration and cell invasion, which may be conducted by suppression of MMP-2/MMP-9 activities. Significant evidence has shown that galectin-3 is implicated in modulation of tumor cells growth. In our study, galectin-3 knockdown reduced cell growth of prostate cancer PC3 cells and induced cell cycle arrest at G1 phase. The G1 cell cycle arrest seemed to be due to up-regulation of p21 expression and its nuclear localization, moreover, downstream pRb displayed hypo-phosphorylation which inhibits the transcription of genes required to traverse G1 to S phase. A relationship of galectin-3 expression with tumorigenic phenotype of many cancer cells has been demonstrated. We showed here that PC3 cells with silencing of galectin-3 displayed reduced colony size and efficiency of colony formation in soft agar. Loss of galectin-3 expression also resulted in reduced tumor growth when cells were injected in the ventral prostate of nude mice. Taken together with observations in other tumor types, it could be postulated that galectin-3 expression is associated with maintenance of tumorigenic potential of cancer cells.

In conclusion, our data show that galectin-3 is cleaved during the progression of prostate cancer and might be associated with metastasis, cell growth, and tumorigenicity of PC3 cells. Expression of intact versus cleaved galectin-3 thus might be used as a marker for prognosis of prostate cancer and a therapeutic target for the treatment of prostate cancer.

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Avraham Raz, MD et al. as part of Beyond the Abstract on UroToday

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