LKB1 inhibits HPV-associated cancer progression by targeting cellular metabolism.
LKB1 inhibits HPV-associated cancer progression by targeting cellular metabolism.
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LKB1 通过靶向细胞代谢来抑制 HPV 相关的癌症进展。
作者：
Zeng Q;Chen J;Li Y;Werle KD;Zhao RX;Quan CS;Wang YS;Zhai YX;Wang JW;Youssef M;Cui R;Liang J;Genovese N;Chow LT;Li YL;Xu ZX
肝激酶 B1 (LKB1) 在黑斑息肉综合征和包括人乳头瘤病毒 (HPV) 引起的宫颈癌在内的多种癌症中发生突变失活。然而，LKB1 突变在宫颈癌发生和进展中的重要性尚未得到研究。在此，我们证明，在小鼠胚胎成纤维细胞中，LKB1 的缺失和 HPV16 E6/E7 的转导对抑制细胞衰老同时促进细胞增殖并增加葡萄糖消耗、乳酸产生和 ATP 产生具有附加作用。 LKB1 的敲低增加了 HPV 转化细胞中的糖酵解、贴壁独立细胞生长以及细胞迁移和侵袭，而 LKB1 的异位表达则减少了。在同系小鼠的肿瘤发生和肺转移模型中，LKB1的缺失显着增加了肺中的肿瘤转移集落，而不影响皮下肿瘤的生长。我们发现 HPV16 E6/E7 通过升高 c-MYC 来增强糖酵解途径中己糖激酶-II (HK-II) 的表达。异位 LKB1 随糖酵解一起减少 HK-II。在正常和 HPV 相关宫颈病变中也观察到 HK-II 和 LKB1 之间的负相关关系。我们认为 LKB1 可以作为防止 HPV 刺激的有氧糖酵解和肿瘤进展的保障措施。这些发现最终可能有助于通过靶向细胞代谢来制定 HPV 相关恶性肿瘤的治疗策略。
Liver kinase B1 (LKB1) is mutationally inactivated in Peutz-Jeghers syndrome and in a variety of cancers including human papillomavirus (HPV)-caused cervical cancer. However, the significance of LKB1 mutations in cervical cancer initiation and progress has not been examined. Herein, we demonstrated that, in mouse embryonic fibroblasts, loss of LKB1 and transduction of HPV16 E6/E7 had an additive effect on constraining cell senescence while promoting cell proliferation and increasing glucose consumption, lactate production, and ATP generation. Knock-down of LKB1 increased and ectopic expression of LKB1 decreased glycolysis, anchorage-independent cell growth, and cell migration and invasion in HPV transformed cells. In the tumorigenesis and lung metastasis model in syngeneic mice, depletion of LKB1 markedly increased tumor metastatic colonies in lungs without affecting subcutaneous tumor growth. We showed that HPV16 E6/E7 enhanced the expression of hexokinase-ll (HK-II) in the glycolytic pathway through elevated c-MYC. Ectopic LKB1 reduced HK-II along with glycolysis. The inverse relationship between HK-II and LKB1 was also observed in normal and HPV-associated cervical lesions. We propose that LKB1 acts as a safeguard against HPV-stimulated aerobic glycolysis and tumor progression. These findings may eventually aid in the development of therapeutic strategy for HPV-associated malignancies by targeting cell metabolism.