Triple knockdown of CDC37, HSP90-alpha and HSP90-beta diminishes extracellular vesicles-driven malignancy events and macrophage M2 polarization in oral cancer

被引：70

作者：

Ono, Kisho ^{[1
,2
]}

Sogawa, Chiharu ^{[1
]}

Kawai, Hotaka ^{[3
]}

Tran, Manh Tien ^{[1
]}

Taha, Eman A. ^{[1
]}

Lu, Yanyin ^{[1
]}

Oo, May Wathone ^{[3
]}

Okusha, Yuka ^{[1
]}

Okamura, Hirohiko ^{[4
]}

Ibaragi, Soichiro

Takigawa, Masaharu ^{[5
]}

Kozaki, Ken-Ichi ^{[1
]}

Nagatsuka, Hitoshi ^{[3
,5
]}

Sasaki, Akira ^{[6
]}

Okamoto, Kuniaki ^{[1
]}

Calderwood, Stuart K. ^{[7
]}

Eguchi, Takanori ^{[1
,5
]}

机构：

[1] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Dent Pharmacol, Okayama, Japan

[2] Okayama Univ Hosp, Dept Oral & Maxillofacial Surg, Okayama, Japan

[3] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Oral Pathol & Med, Okayama, Japan

[4] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Oral Morphol, Okayama, Japan

[5] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Adv Res Ctr Oral & Craniofacial Sci, Okayama, Japan

[6] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Oral & Maxillofacial Surg, Okayama, Japan

[7] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02115 USA

来源：

JOURNAL OF EXTRACELLULAR VESICLES | 2020年 / 9卷 / 01期

关键词：

Extracellular vesicles; epithelial-mesenchymal transition; tumour-associated macrophage; CDC37; HSP90; tetraspanin; oral cancer; NF-KAPPA-B; HEAT-SHOCK PROTEINS; MESENCHYMAL TRANSITION; GASTRIC-CANCER; SECRETED HSP90; EXOSOMES; ANTIGEN; RECEPTOR; GROWTH; CELLS;

D O I：

10.1080/20013078.2020.1769373

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Evidence has been accumulating to indicate that extracellular vesicles (EVs), including exosomes, released by cancer cells can foster tumour progression. The molecular chaperones - CDC37, HSP90 alpha and HSP90 beta play key roles in cancer progression including epithelial-mesenchymal transition (EMT), although their contribution to EVs-mediated cell-cell communication in tumour microenvironment has not been thoroughly examined. Here we show that triple depletion of the chaperone trio attenuates numerous cancer malignancy events exerted through EV release. Metastatic oral cancer-derived EVs (MEV) were enriched with HSP90 alpha HSP90 beta and cancer-initiating cell marker CD326/EpCAM. Depletion of these chaperones individually induced compensatory increases in the other chaperones, whereas triple siRNA targeting of these molecules markedly diminished the levels of the chaperone trio and attenuated EMT. MEV were potent agents in initiating EMT in normal epithelial cells, a process that was attenuated by the triple chaperone depletion. The migration, invasion, and in vitro tumour initiation of oral cancer cells were significantly promoted by MEV, while triple depletion of CDC37/HSP90 alpha/beta reversed these MEV-driven malignancy events. In metastatic oral cancer patient-derived tumours, HSP90 beta was significantly accumulated in infiltrating tumour-associated macrophages (TAM) as compared to lower grade oral cancer cases. HSP90-enriched MEV-induced TAM polarization to an M2 phenotype, a transition known to support cancer progression, whereas the triple chaperone depletion attenuated this effect. Mechanistically, the triple chaperone depletion in metastatic oral cancer cells effectively reduced MEV transmission into macrophages. Hence, siRNA-mediated knockdown of the chaperone trio (CDC37/HSP90 alpha/HSP90 beta) could potentially be a novel therapeutic strategy to attenuate several EV-driven malignancy events in the tumour microenvironment.

引用

页数：21

共 79 条

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