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CD44v、S1PR1、HER3、MET和癌症相关氨基酸转运蛋白是使用单克隆抗体表征的胰腺癌的有前景的靶点。

CD44v, S1PR1, HER3, MET and cancer-associated amino acid transporters are promising targets for the pancreatic cancers characterized using mAb.

作者信息

Nakano Takashi, Okita Kouki, Okazaki Shogo, Yoshimoto Soshi, Masuko Sachiko, Yagi Hideki, Kato Kazunori, Tomioka Yoshihisa, Imai Kenichi, Hamada Yoichi, Masuko Kazue, Shimada-Takaura Kayoko, Nagai Noriaki, Saya Hideyuki, Arai Tomio, Ishiwata Toshiyuki, Masuko Takashi

机构信息

Cell Biology Laboratory, School of Pharmacy, Kindai University, Higashiosaka-shi, Japan.

Faculty of Health and Sports Sciences, Toyo University, Kita-ku, Japan.

出版信息

FEBS Open Bio. 2025 May;15(5):867-884. doi: 10.1002/2211-5463.13963. Epub 2025 Jan 5.

DOI:10.1002/2211-5463.13963
PMID:39757718
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12051033/
Abstract

Effective therapies have yet to be established for pancreatic ductal adenocarcinomas (PDAC) even though it is the most aggressive cancer. In the present study, PDAC was analyzed using novel rat mAbs against membrane proteins in conjunction with flow cytometry and immunohistochemistry. Human epidermal growth receptor (HER)1-4, mesenchymal to epithelial transition factor (MET), sphingosine-1-phospahate receptor 1 (S1PR1), l-type amino acid transporter 1 (LAT1), system x transporter (xCT), alanine-serine-cysteine transporter (ASCT2), cationic amino acid transporter 1 (CAT1) and variant CD44 (CD44v) were expressed at high frequencies in both in vitro and in vivo PDAC. Internalization of membrane proteins by mAbs and growth inhibition by toxin-linked mAbs were demonstrated in many PDAC cell lines, and mAbs against S1PR1, ASCT2, HER3 and CD44v inhibited the growth of xenografted MIA PaCa-2 PDAC cells. Furthermore, CD44v-high PDAC showed high mRNA expression of HER1-3, MET and CD44v, and was correlated with poor prognosis. Taken together, our results suggest that CD44v, S1PR1, HER3, MET and the above-mentioned cancer-associated amino acid transporters might be promising targets for the diagnosis and treatment of PDAC.

摘要

尽管胰腺导管腺癌（PDAC）是最具侵袭性的癌症，但尚未确立有效的治疗方法。在本研究中，我们使用针对膜蛋白的新型大鼠单克隆抗体结合流式细胞术和免疫组织化学对PDAC进行了分析。人表皮生长因子受体（HER）1-4、间充质向上皮转化因子（MET）、1-磷酸鞘氨醇受体1（S1PR1）、L型氨基酸转运体1（LAT1）、xCT转运体系统（xCT）、丙氨酸-丝氨酸-半胱氨酸转运体（ASCT2）、阳离子氨基酸转运体1（CAT1）和可变CD44（CD44v）在体外和体内的PDAC中均高频率表达。在许多PDAC细胞系中均证实了单克隆抗体介导的膜蛋白内化以及毒素连接的单克隆抗体对细胞生长的抑制作用，并且针对S1PR1、ASCT2、HER3和CD44v的单克隆抗体可抑制异种移植的MIA PaCa-2 PDAC细胞的生长。此外，CD44v高表达的PDAC显示HER1-3、MET和CD44v的mRNA高表达，且与预后不良相关。综上所述，我们的结果表明，CD44v、S1PR1、HER3、MET以及上述癌症相关氨基酸转运体可能是PDAC诊断和治疗的有前景的靶点。

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