Development and characterization of carboxy-terminus specific monoclonal antibodies for understanding MUC16 cleavage in human ovarian cancer.
Development and characterization of carboxy-terminus specific monoclonal antibodies for understanding MUC16 cleavage in human ovarian cancer.
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DOI：
10.1371/journal.pone.0193907
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Jain M
中科院分区：
文献类型：
--
作者：
Aithal A;Junker WM;Kshirsagar P;Das S;Kaur S;Orzechowski C;Gautam SK;Jahan R;Sheinin YM;Lakshmanan I;Ponnusamy MP;Batra SK;Jain M
MUC16在卵巢癌中过度表达，在侵袭和转移中发挥重要作用。先前描述的针对细胞表面表达的 MUC16 的单克隆抗体可识别癌抗原 125 (CA125) 中存在的 N 端串联重复表位。 MUC16 在特定位置被切割，从而将 CA125 释放到细胞外空间。最近的报告表明，MUC16 保留的羧基末端 (CT) 片段可能在多种癌症的致瘤性中发挥重要作用。然而，关于癌细胞表面 CT 碎片的命运和存在的数据有限。在此，我们表征了两种单克隆抗体 (mAb)，它们对 MUC16 保留的近膜区域表现出特异性。我们首次证明 MUC16 在卵巢癌细胞 (NIH:OVCAR-3 [OVCAR-3]) 中被裂解，并且裂解的 MUC16 亚基仍然相互关联。对不同级别卵巢肿瘤组织的免疫组织化学分析表明 CA125 和 MUC16 CT mAb 的反应性不同。 CA125 (M11) mAb 检测出 32/40 (80%) 的卵巢癌病例，而 CT mAb (5E6) 检测出 33/40 (82.5%) 的卵巢癌病例。对于浆液性和浆液性乳头状病例，CA125 (M11) mAb 对 27/31 例 (87%) 进行染色，而 CT mAb (5E6) 对 29/31 例 (93.5%) 进行染色。 CT mAb 可以准确预测 MUC16 的表达，因为它们的表位不是串联重复的，并且它们的反应性可能不依赖于 O-连接糖基化。这些抗体可以作为了解 MUC16 裂解的有价值的试剂，也可以作为治疗卵巢癌的潜在治疗剂。
MUC16 is overexpressed in ovarian cancer and plays important roles in invasion and metastasis. Previously described monoclonal antibodies against cell surface expressed MUC16 recognize the N-terminal tandemly repeated epitopes present in cancer antigen 125 (CA125). MUC16 is cleaved at a specific location, thus, releasing CA125 into the extracellular space. Recent reports have indicated that the retained carboxy-terminal (CT) fragment of MUC16 might play an important role in tumorigenicity in diverse types of cancers. However, limited data is available on the fate and existence of CT fragment on the surface of the cancer cell. Herein, we characterize two monoclonal antibodies (mAbs) showing specificity to the retained juxtamembrane region of MUC16. For the first time, we demonstrate that MUC16 is cleaved in ovarian cancer cells (NIH:OVCAR-3 [OVCAR-3]) and that the cleaved MUC16 subunits remain associated with each other. Immunohistochemical analyses on different grades of ovarian tumor tissues indicated differential reactivity of CA125 and MUC16 CT mAbs. The CA125 (M11) mAb detected 32/40 (80%), while the CT mAb (5E6) detected 33/40 (82.5%) of total ovarian cancer cases. For serous and serous papillary cases, the CA125 (M11) mAb stained 27/31 cases (87%), while CT mAb (5E6) stained 29/31 cases (93.5%). The CT mAb(s) accurately predict expression of MUC16 since their epitopes are not tandemly repeated and their reactivity may not be dependent on O-linked glycosylation. These antibodies can serve as valuable reagents for understanding MUC16 cleavage and may also serve as potential therapeutic agents for treatment of ovarian cancer.
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影响因子：
4
作者：
Seelenmeyer, C;Wegehingel, S;Nickel, W
通讯作者：
Nickel, W
影响因子：
--
作者：
Das S;Rachagani S;Torres-Gonzalez MP;Lakshmanan I;Majhi PD;Smith LM;Wagner KU;Batra SK
通讯作者：
Batra SK
影响因子：
37.3
作者：
Felder M;Kapur A;Gonzalez-Bosquet J;Horibata S;Heintz J;Albrecht R;Fass L;Kaur J;Hu K;Shojaei H;Whelan RJ;Patankar MS
通讯作者：
Patankar MS
影响因子：
4.8
作者：
Rump, A;Morikawa, Y;Miyajima, A
通讯作者：
Miyajima, A
影响因子：
8.8
作者：
Comamala, M.;Pinard, M.;Theriault, C.;Matte, I.;Albert, A.;Boivin, M.;Beaudin, J.;Piche, A.;Rancourt, C.
通讯作者：
Rancourt, C.