Restoring FAS Expression via Lipid-Encapsulated FAS DNA Nanoparticle Delivery Is Sufficient to Suppress Colon Tumor Growth In Vivo.
Restoring FAS Expression via Lipid-Encapsulated FAS DNA Nanoparticle Delivery Is Sufficient to Suppress Colon Tumor Growth In Vivo.
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通过脂质包封的FAS DNA纳米颗粒递送恢复FAS表达足以抑制体内结肠肿瘤生长。
DOI：
10.3390/cancers14020361
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发表时间：
2022-01-12
期刊：
影响因子：
5.2
通讯作者：
Liu K
中科院分区：
文献类型：
--
作者：
Merting AD;Poschel DB;Lu C;Klement JD;Yang D;Li H;Shi H;Chapdelaine E;Montgomery M;Redman MT;Savage NM;Nayak-Kapoor A;Liu K
人类结直肠肿瘤的一个关键特征是FAS表达缺失。FAS是活化T细胞FASL的死亡受体。因此，FAS表达的缺失可能促进肿瘤细胞的免疫逃逸。我们的目的是确定恢复FAS表达是否足以抑制结直肠肿瘤的生长。合成小鼠和人FAS cDNA并包封到阳离子脂质纳米粒dotap -胆固醇中，分别制备dotap -胆- mfas和dotap -胆- hfas。恢复转移小鼠结肠肿瘤细胞中FAS的表达，可以在体外消除fasl诱导的FAS+肿瘤细胞，并在体内抑制荷瘤小鼠结肠肿瘤的生长和进展。体外恢复FAS表达诱导转移性人结肠癌细胞FAS受体自寡聚化和肿瘤细胞自凋亡dotap - cholo - hfas治疗也足以抑制胸腺小鼠转移性结肠癌异种移植物的生长。肿瘤选择性递送FAS DNA纳米颗粒可能是治疗人类结直肠癌的有效方法。人类结直肠癌的一个标志是细胞毒性T淋巴细胞（ctl） FASL的死亡受体FAS的表达缺失。然而，仅恢复FAS表达是否足以抑制结直肠癌的发展尚不清楚。在人类结直肠癌中，FAS启动子高甲基化并与FAS mRNA水平呈负相关。单细胞RNA-Seq数据集分析显示，FAS在人结直肠癌患者的上皮细胞和免疫细胞中高表达，但在结肠肿瘤细胞中低表达。设计合成密码子使用优化的小鼠和人FAS cDNA，并将其包封到阳离子脂质中，分别制备纳米粒dotap - choll - mfas和dotap - choll - hfas。在转移小鼠结肠肿瘤细胞中过表达经密码子使用优化的FAS，可使fasl诱导的FAS+肿瘤细胞在体外消除，抑制结肠肿瘤生长，提高荷瘤小鼠的体内存活率。密码子优化FAS诱导的FAS受体自寡聚化和肿瘤细胞自身凋亡在转移性人结肠癌细胞中的过度表达。dotap - cholo - hfas治疗也足以抑制胸腺小鼠转移性结肠癌异种移植物的生长。dotap - choll - mfas治疗无明显肝毒性。我们的数据表明，肿瘤选择性递送FAS DNA纳米颗粒足以抑制体内人类结肠肿瘤的生长。
A key feature of human colorectal tumor is loss of FAS expression. FAS is the death receptor for FASL of activated T cells. Loss of FAS expression therefore may promote tumor cell immune escape. We aimed at determining whether restoring FAS expression is sufficient to suppress colorectal tumor growth. Mouse and human FAS cDNA was synthesized and encapsulated into cationic lipid nanoparticle DOTAP-Cholesterol to formulate DOTAP-Chol-mFAS and DOTAP-Chol-hFAS, respectively. Restoring FAS expression in metastatic mouse colon-tumor cells enabled FASL-induced elimination of FAS+ tumor cells in vitro and suppressed colon-tumor growth and progression in tumor-bearing mice in vivo. Restoring FAS expression induced FAS receptor auto-oligomerization and tumor cell auto-apoptosis in metastatic human colon-tumor cells in vitro. DOTAP-Chol-hFAS therapy is also sufficient to suppress metastatic human colon tumor xenograft growth in athymic mice. Tumor-selective delivery of FAS DNA nanoparticle is potentially an effective therapy for human colorectal cancer. A hallmark of human colorectal cancer is lost expression of FAS, the death receptor for FASL of cytotoxic T lymphocytes (CTLs). However, it is unknown whether restoring FAS expression alone is sufficient to suppress csolorectal-cancer development. The FAS promoter is hypermethylated and inversely correlated with FAS mRNA level in human colorectal carcinomas. Analysis of single-cell RNA-Seq datasets revealed that FAS is highly expressed in epithelial cells and immune cells but down-regulated in colon-tumor cells in human colorectal-cancer patients. Codon usage-optimized mouse and human FAS cDNA was designed, synthesized, and encapsulated into cationic lipid to formulate nanoparticle DOTAP-Chol-mFAS and DOTAP-Chol-hFAS, respectively. Overexpression of codon usage-optimized FAS in metastatic mouse colon-tumor cells enabled FASL-induced elimination of FAS+ tumor cells in vitro, suppressed colon tumor growth, and increased the survival of tumor-bearing mice in vivo. Overexpression of codon-optimized FAS-induced FAS receptor auto-oligomerization and tumor cell auto-apoptosis in metastatic human colon-tumor cells. DOTAP-Chol-hFAS therapy is also sufficient to suppress metastatic human colon tumor xenograft growth in athymic mice. DOTAP-Chol-mFAS therapy exhibited no significant liver toxicity. Our data determined that tumor-selective delivery of FAS DNA nanoparticles is sufficient for suppression of human colon tumor growth in vivo.
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影响因子：
64.8
作者：
通讯作者：
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