Department of Oncology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Shenyang, 110022, Liaoning, China.
Department of Endocrinology, Northern Theater Air Force Hospital of the People's Liberation Army, Shenyang, Liaoning, China.
Mol Cell Biochem. 2022 Dec;477(12):2801-2816. doi: 10.1007/s11010-022-04480-7. Epub 2022 Jun 1.
Previous studies reported that cancer stem cells (CSCs) might be responsible for drug resistance and cancer progression. Transformation-Related Gene 16 Protein (TRG16), a pseudokinase, was reported to be a suppressor in some types of cancer and its overexpression impaired hepatocellular carcinoma cell stemness. However, the function of TRG16 in BC remains unclear. We found that TRG16 expression was significantly downregulated in BC tissues compared with adjacent tissues (n = 40; P < 0.001) and BC patients with lower expression of TRG16 had a worse prognosis. Forced expression of TRG16 inhibited BC stem cell-like properties as evidenced by decreased CD44-positive cells (CSC marker), reduced mammosphere quantity, and downregulated Nanog, aldehyde dehydrogenase, octamer-binding transcription factor 4, and SRY-box transcription factor 2 expression (CSC markers). Moreover, TRG16 overexpression inhibited self-renewal and invasion capabilities of BC cells in vitro as well as tumor growth in vivo but increased cisplatin sensitivity. However, TRG16 silencing had the opposite effects. Further mechanistic studies revealed that TRG16 was targeted and negatively regulated by miR-765, a facilitator of BC progression. TRG16 could suppress the activation of the NF-κB pathway in BC cells, which is a positive pathway in BC progression and contributes to the maintenance of cancer cell stemness. In conclusion, the results above demonstrate that TRG16, negatively regulated by miR-765, may inhibit the BC progression by regulating BC stem cell-like properties and this inhibition may be mediated by the NF-κB pathway. Our findings indicate that TRG16 may be a potential therapeutic targetable node for BC. TRG16, negatively regulated by miR-765, may inhibit the BC progression through regulating BC stem cell-like properties and this inhibition may be mediated by the NF-κB pathway.
先前的研究报告称，癌症干细胞（CSCs）可能是导致药物耐药和癌症进展的原因。转化相关基因 16 蛋白（TRG16）是一种拟激酶，据报道在某些类型的癌症中是一种抑制物，其过表达会损害肝癌细胞的干细胞特性。然而，TRG16 在乳腺癌中的功能尚不清楚。我们发现，与相邻组织相比（n=40；P<0.001），乳腺癌组织中 TRG16 的表达明显下调，并且 TRG16 表达较低的乳腺癌患者预后更差。TRG16 的强制表达抑制了乳腺癌干细胞样特性，表现为 CD44 阳性细胞（CSC 标志物）减少、乳腺球数量减少以及 Nanog、醛脱氢酶、八聚体结合转录因子 4 和性决定区 Y 框转录因子 2 的表达下调（CSC 标志物）。此外，TRG16 过表达可抑制乳腺癌细胞在体外的自我更新和侵袭能力以及体内肿瘤生长，但增加了顺铂的敏感性。然而，TRG16 沉默则有相反的效果。进一步的机制研究表明，TRG16 是 miR-765 的靶标，miR-765 是乳腺癌进展的促进因子。TRG16 可以抑制乳腺癌细胞中 NF-κB 通路的激活，该通路在乳腺癌进展中是一个正通路，有助于维持癌细胞的干细胞特性。总之，上述结果表明，受 miR-765 负调控的 TRG16 可能通过调节乳腺癌干细胞样特性来抑制乳腺癌的进展，这种抑制可能是由 NF-κB 通路介导的。我们的研究结果表明，TRG16 可能是一个有潜力的乳腺癌治疗靶点。受 miR-765 负调控的 TRG16 可能通过调节乳腺癌干细胞样特性来抑制乳腺癌的进展，这种抑制可能是由 NF-κB 通路介导的。
