Zhou Kening, Lin Jing, Dai Mimi, He Yingying, Xu Jingui, Lin Qian
Department of Gynaecology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, 100 Minjiang Dadao, West District, Quzhou City, 324000, Zhejiang Province, China.
Department of Pathology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou City, China.
J Bioenerg Biomembr. 2021 Dec;53(6):703-713. doi: 10.1007/s10863-021-09924-1. Epub 2021 Nov 3.
Endometrial cancer (EC) is a common gynecological malignant tumor worldwide. It is imperative to study pathogenesis and therapeutic targets for improving the prognosis of EC. The present study aimed to explore the function and mechanism of kinesin family member C1 (KIFC1) in EC. EC tumor and adjacent normal tissues were collected from 68 pairs of patients. The expression of KIFC1 in tissues and EC cells was analyzed by immunohistochemistry, qRT-PCR or western blot. MTT assay was used to test the cell viability. Flow cytometry was used to determine apoptosis and the cell cycle. Glucose uptake, lactate production, ATP contents and lactate dehydrogenase (LDH) activity were evaluated by a glucose metabolism kit. The expression of HMGA1, c-myc and glycolytic genes was assessed using western blot or qRT-PCR. A mouse xenograft model was established in BALB/c mice to detect tumor growth in vivo. KIFC1 was significantly upregulated in EC tumor tissues compared to adjacent normal control tissues. The upregulated expression of KIFC1 was correlated with poor prognosis in patients. Lentiviral-mediated overexpression of KIFC1 observably enhanced cell viability and reduced the apoptotic rate of Ishikawa and HEC-1B cells. Cell cycle progression was also expedited in the KIFC1 vector group. Moreover, overexpression of KIFC1 elevated glucose uptake, lactate production, ATP contents and LDH activity. However, knockdown of KIFC1 by short hairpin RNA (shRNA) showed the reverse effect on cellular functions. In addition, the expression of c-myc, GLUT1, LDHA and HK2 was increased by the KIFC1 vector. Moreover, HMGA1 regulated the expression of c-myc and glycolytic genes. Upregulated HMGA1 could rescue the effect of KIFC1 knockdown on cellular functions and the expression of glycolytic genes. Finally, KIFC1 knockdown inhibits tumor growth in vivo. The upregulation of KIFC1 was correlated with poor prognosis in EC. KIFC1 promoted aerobic glycolysis in endometrial cancer cells by regulating the HMGA1/c-myc pathway. KIFC1 may be a potential target for the diagnosis and therapy of EC.
子宫内膜癌（EC）是全球常见的妇科恶性肿瘤。研究其发病机制和治疗靶点对于改善EC的预后至关重要。本研究旨在探讨驱动蛋白家族成员C1（KIFC1）在EC中的功能及机制。收集68对患者的EC肿瘤组织及相邻正常组织。采用免疫组织化学、qRT-PCR或蛋白质免疫印迹法分析KIFC1在组织及EC细胞中的表达。采用MTT法检测细胞活力。通过流式细胞术测定细胞凋亡及细胞周期。使用葡萄糖代谢试剂盒评估葡萄糖摄取、乳酸生成、ATP含量及乳酸脱氢酶（LDH）活性。采用蛋白质免疫印迹法或qRT-PCR评估HMGA1、c-myc及糖酵解相关基因的表达。在BALB/c小鼠中建立小鼠异种移植模型以检测体内肿瘤生长。与相邻正常对照组织相比，KIFC1在EC肿瘤组织中显著上调。KIFC1表达上调与患者预后不良相关。慢病毒介导的KIFC1过表达显著增强了Ishikawa和HEC-1B细胞的活力并降低了其凋亡率。KIFC1载体组的细胞周期进程也加快。此外，KIFC1过表达提高了葡萄糖摄取、乳酸生成、ATP含量及LDH活性。然而，短发夹RNA（shRNA）敲低KIFC1对细胞功能产生相反影响。此外，KIFC1载体增加了c-myc、GLUT1、LDHA和HK2的表达。此外，HMGA1调节c-myc及糖酵解相关基因的表达。上调的HMGA1可挽救KIFC1敲低对细胞功能及糖酵解相关基因表达的影响。最后，敲低KIFC1可抑制体内肿瘤生长。KIFC1上调与EC患者预后不良相关。KIFC1通过调节HMGA1/c-myc途径促进子宫内膜癌细胞的有氧糖酵解。KIFC1可能是EC诊断和治疗的潜在靶点。
