Wu Zi-Yi, He Yong-Qiao, Wang Tong-Min, Yang Da-Wei, Li Dan-Hua, Deng Chang-Mi, Cao Lian-Jing, Zhang Jiang-Bo, Xue Wen-Qiong, Jia Wei-Hua
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
School of Public Health, Sun Yat-sen University, Guangzhou, China.
Front Cell Dev Biol. 2021 Dec 13;9:763875. doi: 10.3389/fcell.2021.763875. eCollection 2021.
Oncofetal chondroitin sulfate expression plays an important role in the development of tumors and the pathogenesis of malaria in pregnancy. However, the biosynthesis and functions of these chondroitin sulfates, particularly the tissue-specific regulation either in tumors or placenta, have not been fully elucidated. Here, by examining the glycogenes availability in chondroitin sulfate biosynthesis such as xylosytransferase, chondroitin synthase, sulfotransferase, and epimerase, the conserved or differential CS glycosylation in normal, colorectal cancer (CRC), and placenta tissue were predicted. We found that the expression of seven chondroitin sulfate biosynthetic enzymes, namely B4GALT7, B3GALT6, B3GAT3, CHSY3, CHSY1, CHPF, and CHPF2, were significantly increased, while four other enzymes (XYLT1, CHST7, CHST15, and UST) were decreased in the colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ) patients. In the human placenta, where the distinct chondroitin sulfate is specifically bound with VAR2CSA on parasite-infected RBC, eight chondroitin sulfate biosynthesis enzymes (CSGALNACT1, CSGALNACT2, CHSY3, CHSY1, CHPF, DSE, CHST11, and CHST3) were significantly higher than the normal colon tissue. The similarly up-regulated chondroitin synthases (CHSY1, CHSY3, and CHPF) in both cancer tissue and human placenta indicate an important role of the proteoglycan CS chains length for VAR2CSA protein binding. Interestingly, twelve highly expressed chondroitin sulfate enzymes were significantly correlated to worse outcomes (prognosis) in both COAD and READ. Furthermore, we showed that the levels of chondroitin sulfate enzymes are significantly correlated with the expression of immuno-regulators and immune infiltration levels in CRCs and placenta, and involved in multiple essential pathways, such as extracellular matrix organization, epithelial-mesenchymal transition, and cell adhesion. Our study provides novel insights into the oncofetal chondroitin sulfate biosynthesis regulation and identifies promising targets and biomarkers of immunotherapy for CRC and malaria in pregnancy.
癌胚硫酸软骨素的表达在肿瘤发展和妊娠疟疾发病机制中发挥重要作用。然而，这些硫酸软骨素的生物合成和功能，特别是在肿瘤或胎盘中的组织特异性调控，尚未完全阐明。在此，通过检测硫酸软骨素生物合成中木糖基转移酶、硫酸软骨素合酶、硫酸转移酶和表异构酶等糖基因的可用性，预测了正常、结直肠癌（CRC）和胎盘组织中保守或差异的CS糖基化。我们发现，在结肠腺癌（COAD）和直肠腺癌（READ）患者中，七种硫酸软骨素生物合成酶，即B4GALT7、B3GALT6、B3GAT3、CHSY3、CHSY1、CHPF和CHPF2的表达显著增加，而其他四种酶（XYLT1、CHST7、CHST15和UST）的表达则降低。在人类胎盘中，特定的硫酸软骨素与寄生虫感染红细胞上的VAR2CSA特异性结合，八种硫酸软骨素生物合成酶（CSGALNACT1、CSGALNACT2、CHSY3、CHSY1、CHPF、DSE、CHST11和CHST3）显著高于正常结肠组织。癌组织和人类胎盘中硫酸软骨素合酶（CHSY1、CHSY3和CHPF）的类似上调表明蛋白聚糖CS链长度对VAR2CSA蛋白结合具有重要作用。有趣的是，在COAD和READ中，十二种高表达的硫酸软骨素酶与较差的预后显著相关。此外，我们表明硫酸软骨素酶的水平与CRCs和胎盘中免疫调节因子的表达及免疫浸润水平显著相关，并参与多种重要途径，如细胞外基质组织、上皮-间质转化和细胞粘附。我们的研究为癌胚硫酸软骨素生物合成调控提供了新见解，并确定了CRC和妊娠疟疾免疫治疗的有前景的靶点和生物标志物。
