SNHG3 Functions as miRNA Sponge to Promote Breast Cancer Cells Growth Through the Metabolic Reprogramming
SNHG3 Functions as miRNA Sponge to Promote Breast Cancer Cells Growth Through the Metabolic Reprogramming
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DOI：
10.1007/s12010-020-03244-7
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发表时间：
2020-01-20
影响因子：
3
通讯作者：
Li, Xun
中科院分区：
文献类型：
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作者：
Li, Yan;Zhao, Zhenhui;Li, Xun
癌相关成纤维细胞（CAFs）是肿瘤微环境的重要组成部分。CAFs和癌细胞之间的动态相互作用在肿瘤的发生和发展过程中起着至关重要的作用。然而，CAFs和癌细胞之间的细胞间通讯机制在很大程度上仍然未知。我们通过透射电子显微镜表征了从乳腺癌患者来源的CAF分泌的外泌体。通过实时定量PCR和免疫印迹检测SNHG 3、miR-330- 5 p和PKM（丙酮酸激酶M1/M2）的表达。通过CCK 8和线粒体耗氧实验检测SNHG 3对肿瘤细胞生长和代谢的影响。SNHG 3、miR-330- 5 p和PKM之间的结合通过双荧光素酶报告基因测定来检查。进行乳腺肿瘤原位异种移植实验以确定SNHG 3的体内功能。我们证明了CAFs分泌的外泌体在肿瘤细胞摄取外泌体后会重新编程代谢途径。CAF分泌的外泌体lncRNA SNHG 3在乳腺癌细胞中充当miR-330- 5 p的分子海绵。在乳腺癌细胞中，PKM可被miR-330- 5 p靶向，并受SNHG 3调控。在机制上，在CAF分泌的外泌体中的SNHG 3敲低通过肿瘤细胞中miR-330- 5 p的增加和PKM表达的减少来抑制糖酵解代谢和细胞增殖。SNHG 3作为miR-330- 5 p海绵发挥作用，积极调节PKM表达，抑制线粒体氧化磷酸化，增加糖酵解羧化，并增强乳腺肿瘤细胞增殖。总体而言，SNHG 3可能在乳腺癌的发展和进展中发挥重要作用，并支持癌细胞和肿瘤微环境之间靶向通讯的治疗潜力。
Cancer-associated fibroblasts (CAFs) are important ingredient in tumor microenvironment. The dynamic interplay between CAFs and cancer cells plays essential roles during tumor development and progression. However, the mechanisms of intercellular communication between CAFs and cancer cells remain largely unknown. We characterized exosomes secreted from breast cancer patient-derived CAFs by transmission electron microscopy. The expression of SNHG3, miR-330-5p, and PKM (Pyruvate Kinase M1/M2) was examined by real-time QPCR and immunoblot. The function of SNHG3 on the growth and metabolism of tumor cells was used by CCK8 and mitochondrial oxygen consumption assays. The binding between SNHG3, miR-330-5p, and PKM was examined by dual luciferase reporter assays. Orthotopical xenograft of breast tumor experiments was performed to determine the function of SNHG3 in vivo. We demonstrated that exosomes secreted from CAFs reprogram the metabolic pathways after tumor cells uptake the exosomes. CAF-secreted exosomal lncRNA SNHG3 served as a molecular sponge for miR-330-5p in breast cancer cells. Moreover, PKM could be targeted by miR-330-5p and was controlled by SNHG3 in breast cancer cells. Mechanistically, SNHG3 knockdown in CAF-secreted exosomes suppressed glycolysis metabolism and cell proliferation by the increase of miR-330-5p and decrease of PKM expression in tumor cells. SNHG3 functions as a miR-330-5p sponge to positively regulate PKM expression, inhibit mitochondrial oxidative phosphorylation, increase glycolysis carboxylation, and enhance breast tumor cell proliferation. Overall, SNHG3 could play a major role in the development and progression of breast cancer and support the therapeutic potential of targeting communication between cancer cells and tumor microenvironment.