Kwon Kyung-Min, Chung Tae-Wook, Kwak Choong-Hwan, Choi Hee-Jung, Kim Kyung-Woon, Ha Sun-Hyung, Cho Seung-Hak, Lee Young-Choon, Ha Ki-Tae, Lee Moon-Jo, Kim Cheorl-Ho
Molecular and Cellular Glycobiology Unit, Department of Biological Sciences, Sungkyunkwan University, Seoburo 2066, Jangan-Gu, Suwon, Gyunggi-Do, 16419, Korea;; Research Institute, Davinch-K Co., Ltd., B1603-3, 606, Seobusaet-gil, Geumcheon-gu, Seoul 153-719, Korea.
Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan City, Gyeongsangnam-Do, Korea.
Int J Biol Sci. 2017 Feb 12;13(3):265-275. doi: 10.7150/ijbs.16903. eCollection 2017.
The disialoganglioside GD3 has been considered to be involved in tumor progression or suppression in various tumor cells. However, the significance of the biological functions of GD3 in breast cancer cells is still controversial. This prompted us to study the possible relationship(s) between GD3 expression and the metastatic potential of a breast cancer MDA-MB231 cells as an estrogen receptor negative (ER-) type. The human GD3 synthase cDNA was transfected into MDA-MB231 cells, and G-418 bulk selection was used to select cells stably overexpressing the GD3 synthase. invasion potentials of the GD3 synthase over-expressing cells (pc3-GD3s) were significantly suppressed when compared with control cells. Expression of intercellular adhesion molecule-1 (ICAM-1; CD54) was down-regulated in the pc3-GD3s cells and the decrease in ICAM-I expression is directly related to the decrease in invasiveness of the pc3-GD3s cells. Another type of ER negative SK-BR3 cells exhibited the similar level of ICAM-1 expression as MDA-MB231 cells, while the ER positive MCF-7 cells (ER+) showed the increased expression level of ICAM-1. Then, we investigated signaling pathways known to control ICAM-1 expression. No difference was observed in the phosphorylation of ERK and p38 between the pc3-GD3s and control cells (pc3), but the activation of AKT was inhibited in pc3-GD3s, and not in the control (pc3). In addition, the composition of total gangliosides was changed between control (pc3) and pc3-GD3s cells, as confirmed by HPTLC. The pc3-GD3s cells had an accumulation of the GD2 instead of the GD3. RT-PCR results showed that not only GD3 synthase, but also GM2/GD2 synthase (β4-GalNc T) expression was increased in pc3-GD3s cells. Overexpression of GD3 synthase suppresses the invasive potential of human breast cancer MDA-MB-231 cells through down-regulation of ICAM-1 and the crucial pathway to allow the apoptotic effect has been attributed to accumulation of the GD2 ganglioside. ER has been linked to the ICAM-1 expression with GD3 to GD2 conversion in human breast cancer cells. This is the first finding of the endogenous sialyltransferase functions in tumor cells.
双唾液酸神经节苷脂GD3被认为与多种肿瘤细胞的肿瘤进展或抑制有关。然而，GD3在乳腺癌细胞中的生物学功能意义仍存在争议。这促使我们研究GD3表达与雌激素受体阴性（ER-）型乳腺癌MDA-MB231细胞转移潜能之间的可能关系。将人GD3合酶cDNA转染到MDA-MB231细胞中，并使用G-418大量筛选来选择稳定过表达GD3合酶的细胞。与对照细胞相比，过表达GD3合酶的细胞（pc3-GD3s）的侵袭潜能显著受到抑制。细胞间粘附分子-1（ICAM-1；CD54）在pc3-GD3s细胞中的表达下调，ICAM-1表达的降低与pc3-GD3s细胞侵袭性的降低直接相关。另一种ER阴性的SK-BR3细胞表现出与MDA-MB231细胞相似水平的ICAM-1表达，而ER阳性的MCF-7细胞（ER+）则表现出ICAM-1表达水平升高。然后，我们研究了已知控制ICAM-1表达的信号通路。在pc3-GD3s细胞和对照细胞（pc3）之间，未观察到ERK和p38磷酸化的差异，但pc3-GD3s细胞中AKT的激活受到抑制，而对照细胞（pc3）中未受抑制。此外，通过高效薄层层析（HPTLC）证实，对照（pc3）细胞和pc3-GD3s细胞之间总神经节苷脂的组成发生了变化。pc3-GD3s细胞中积累的是GD2而不是GD3。逆转录聚合酶链反应（RT-PCR）结果表明，在pc3-GD3s细胞中，不仅GD3合酶，而且GM2/GD2合酶（β4-半乳糖神经酰胺转移酶）的表达也增加。GD3合酶的过表达通过下调ICAM-1抑制人乳腺癌MDA-MB-231细胞的侵袭潜能，并且导致凋亡效应的关键途径归因于GD2神经节苷脂的积累。在人乳腺癌细胞中，ER与ICAM-1表达以及GD3向GD2的转化有关。这是首次在肿瘤细胞中发现内源性唾液酸转移酶的功能。
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