A deeper insight into tumor metastasis mechanism is urgent to provide accurate diagnosis and therapy. Cervical cancer is ranked top in the ranking of female cancer and the metastasis of cervical cancer is one of the main causes of decreasing survival rates. Wherein, neuroendocrine cervical tumor is a violent but rare form of cervical tumor which show at a high danger of disease development as well as recurrence. Based on our previous proteomic study, LGALS1 was selected as a potential disease marker for neuroendocrine cervical cancer.
Previous reports revealed that overexpressed LGALS1 was observed in numerous malignant tumors and LGALS1 was correlated with cancer invasiveness and progression in gastric cancer , thyroid cancer , colorectal cancer . and breast cancer . However, the functional roles of LGALS1 in tumor progression and metastasis of neuroendocrine cervical cancer are rare to be elucidated. Our results demonstrated that the decreased LGALS1 expression significantly reduced cell proliferation and blocked cell cycle progression in both HM-1 and HM-2 cells. These findings implicated LGALS1 in tumor progression as well as to be a potential independent prognostic factor for neuroendocrine cervical cancer. A preceding study indicated that LGALS1 knockdown by gene silencing significantly inhibited cell proliferation in epithelial ovarian cancer in vitro . Another study showed that A2780-1A9 cells treated with OTX008, the LGALS1 inhibitor, lead to the suppression of the AKT and ERK1/2-dependent survival pathways to induce anti-proliferative effects . These results were consistent with the effects of LGALS1 on neuroendocrine cervical cancer cell growth.
The cyclin-dependent kinases CDK4 and CDK6 have been reported to form complex with cyclin D to promote cell proliferation. The predominant cellular target of cyclin D-CDK4/6 complex is the Rb protein, which inhibits cell-cycle progression from G1 to S phase until its inactivation by phosphorylation . Phosphorylated Rb might release E2F transcription factor which can regulate RNA processing, inhibition of apoptosis and proceeding cells into S-phase . Moreover, cyclin E-CDK2 complex plays an important role in the G1-S phase transition through phosphorylation of Rb . In addition, cyclin E-CDK2 complex has been reported to interact p27 leading to ubiquitin-dependent degradation of p27 . Our results demonstrated knockdown of LGALS1 deregulated cell cycle progression and inhibited CDK2/4/6 activity through up-regulation of p27 expression and inactivation of Rb function implying silencing of LGALS1 leads to block of cell cycle in neuroendocrine cervical cancer. Our studies also demonstrated silence of LGALS1 reduced profilin expression followed by reducing migration ability of neuroendocrine cervical cancer cells.
LGALS1 is found both on plasma membrane and in extracellular spaces, the physical interaction between LGALS1 and its associated partners concern downstream signaling events. GM1 ganglioside, extracellular matrix components, H-Ras and integrins are all recognized to be the binding partners of LGALS . Previous studies also revealed that integrin α11β1 , integrin α5β3 (Leblanc R, Lee SC, David M, et al. Interaction of platelet-derived autotaxin with tumor integrin alphaVbeta3 controls metastasis of breast cancer cells to bone. Blood 2014; 124: 3141-3150.) and integrin α2β1  played important roles in promoting cancer metastasis. Additionally, LGALS1 interacted with integrin α6β4 to facilitate cancer metastasis in lung cancer . Based on these studies, we suggest that over-expression of LGALS1 probably activates intracellular signaling to promote neuroendocrine cervical cancer metastasis via integrin signaling pathways. Further studies will be imperative to investigate which types of integrins are involved in the binding of LGALS1, contributing to neuroendocrine cervical cancer metastasis.
In summary, LGALS1 was over-expressed in neuroendocrine cervical cancer. Silencing of LGALS1 can promote neuroendocrine cervical cancer cell apoptosis, cell survival as well as attenuate migration ability of the cells through inhibition of CDK2, CDK4, CDK6, Cyclin D1 and p-Rb. Thus, LGALS1 is potentially to be a candidate to detect and treatment of neuroendocrine cervical cancer.