Yang Hao, Hou Hui, Zhao Haiping, Yu Tianwei, Hu Yuchong, Hu Yue, Guo Junmei
Department of Radiation Oncology, Inner Mongolia Cancer Hospital and Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, China.
Department of Pediatric Hematology and Oncology, Inner Mongolia Autonomous Region People's Hospital, Hohhot, China.
Front Oncol. 2021 Nov 11;11:794015. doi: 10.3389/fonc.2021.794015. eCollection 2021.
The acquisition of cancer stem-like properties is believed to be responsible for cancer metastasis and therapeutic resistance in cervical cancer (CC). CC tissues display a high expression level of hexokinase 2 (HK2), which is critical for the proliferation and migration of CC cells. However, little is known about the functional role of HK2 in the maintenance of cancer stem cell-like ability and cisplatin resistance of CC cells. Here, we showed that the expression of HK2 is significantly elevated in CC tissues, and high HK2 expression correlates with poor prognosis. HK2 overexpression (or knockdown) can promote (or inhibit) the sphere-forming ability and cisplatin resistance in CC cells. In addition, HK2-overexpressing CC cells show enhanced expression of cancer stem cell-associated genes (including and ) and drug resistance-related gene . The expression of HK2 is mediated by miR-145, miR-148a, and miR-497 in CC cells. Overexpression of miR-148a is sufficient to reduce sphere formation and cisplatin resistance in CC cells. Our results elucidate a novel mechanism through which miR-148a regulates CC stem cell-like properties and chemoresistance by interfering with the oncogene , providing the first evidence that dysregulation of the miR-148a/HK2 signaling plays a critical role in the maintenance of sphere formation and cisplatin resistance of CC cells. Our findings may guide future studies on therapeutic strategies that reverse cisplatin resistance by targeting this pathway.
癌症干细胞样特性的获得被认为是宫颈癌（CC）发生转移和产生治疗抗性的原因。CC组织中己糖激酶2（HK2）表达水平较高，这对CC细胞的增殖和迁移至关重要。然而，关于HK2在维持CC细胞的癌症干细胞样能力和顺铂抗性方面的功能作用，人们了解甚少。在此，我们发现CC组织中HK2的表达显著升高，且HK2高表达与预后不良相关。HK2过表达（或敲低）可促进（或抑制）CC细胞的成球能力和顺铂抗性。此外，HK2过表达的CC细胞中癌症干细胞相关基因（包括 和 ）以及耐药相关基因 的表达增强。CC细胞中HK2的表达由miR - 145、miR - 148a和miR - 497介导。miR - 148a过表达足以降低CC细胞的成球能力和顺铂抗性。我们的结果阐明了一种新机制，即miR - 148a通过干扰癌基因 来调节CC干细胞样特性和化疗抗性，首次证明了miR - 148a/HK2信号通路失调在维持CC细胞成球能力和顺铂抗性中起关键作用。我们的发现可能为未来通过靶向该通路逆转顺铂抗性的治疗策略研究提供指导。
