Premature senescence induced by oncogenic stimuli or tumor suppressor activation plays opposing roles in tumorigenesis. Here, we propose that galectin-3, a β-galactoside-binding lectin, regulates premature senescence without oncogenic stress. We detected premature senescence, decreased Skp2, and increased p27 KIP1 expression in galectin-3 knockout MEFs and galectin-3-depleted gastric cancer cells. Interestingly, galectin-3 depletion did not affect other senescence inducers such as p14 ARF, p16 INK4A, and p21 WAF1/CIP1, suggesting that galectin-3-regulated senescence is p27 KIP1 dependent. We demonstrate that galectin-3 depletion decreases retinoblastoma protein (Rb) phosphorylation (Ser780, Ser807/811), cyclin D1 and CDK4 expression, and E2F1 transcriptional activation. Galectin-3 directly interacts with the cyclin D1/CDK4 complex and promotes hyperphosphorylation of Rb. It also blocks the inhibition of E2F1 transcription, thereby increasing the expression of Skp2 and reducing the stability of p27 KIP1 to promote the proliferation of gastric cancer cells. Xenograft mice with galectin-3-depleted gastric cancer cells display tumor growth retardation that is reversed by Skp2 overexpression. Increased expression of galectin-3 is also associated with the advanced TNM (tumor, lymph node, metastasis) system, clinicopathological stage, and lymph node metastases. The probability of survival was significantly decreased in gastric cancer patients with galectin-3 high p27 KIP1-low cells. Taken together, our results show that galectin-3 may accelerate gastric tumorigenesis by inhibiting premature senescence.
Bibliographical noteFunding Information:
Acknowledgements. We are thankful to Dr. FT Liu (UC Davis) for kindly providing the C57BL/6 mice with the galectin-3-knockout allele (male and female mice, homozygous −/−). This research was supported by grants from the Cooperative Research Program for Agricultural Science & Technology Development (PJ008462); the Korea Health Technology R&D Project, Ministry of Health & Welfare (A121982); Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (2012R1A1A2043505); and the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (no. NRF-2011-0030086).
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology