Dysregulation of cholesterol homeostasis occurs in multiple types of tumors and promotes cancer progression. Investigating the specific processes that induce abnormal cholesterol metabolism could identify therapeutic targets to improve cancer treatment. In this investigation, we observed upregulation of 7-dehydrocholesterol reductase (DHCR7), a vital enzyme involved in the synthesis of cholesterol, within bladder cancer (BC) tissues in comparison to normal tissues, which was correlated with increased BC metastasis. Increased expression of DHCR7 in BC was attributed to decreased mRNA degradation mediated by YTHDF2. Loss or inhibition of DHCR7 reduced BC cell invasion in vitro and metastasis in vivo. Mechanistically, DHCR7 promoted BC metastasis by activating the cAMP/PKA/FAK pathway. Specifically, DHCR7 increased cAMP levels by elevating cholesterol content in lipid rafts, thereby facilitating the transduction of signaling pathways mediated by cAMP receptors. DHCR7 additionally enhanced the cAMP signaling pathway by reducing the concentration of 7-DHC and promoting the transcription of the G protein-coupled receptor GIPR. Overall, these findings demonstrate that DHCR7 plays an important role in BC invasion and metastasis by modulating cholesterol synthesis and cAMP signaling. Furthermore, inhibition of DHCR7 shows promise as a viable therapeutic strategy for suppressing BC invasion and metastasis.

中文翻译：

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m6A 介导的 7-脱氢胆固醇还原酶诱导刺激胆固醇合成和 cAMP 信号传导促进膀胱癌转移


胆固醇稳态失调发生在多种类型的肿瘤中，并促进癌症进展。研究诱导胆固醇代谢异常的特定过程可以确定改善癌症治疗的治疗靶点。在这项研究中，我们观察到与正常组织相比，膀胱癌 （BC） 组织内 7-脱氢胆固醇还原酶 （DHCR7） 上调，DHCR7 是一种参与胆固醇合成的重要酶，这与 BC 转移增加相关。DHCR7 在 BC 中表达的增加归因于 YTHDF2 介导的 mRNA 降解减少。DHCR7 的缺失或抑制减少了体外 BC 细胞侵袭和体内转移。从机制上讲，DHCR7 通过激活 cAMP/PKA/FAK 通路促进 BC 转移。具体来说，DHCR7 通过提高脂筏中的胆固醇含量来提高 cAMP 水平，从而促进 cAMP 受体介导的信号通路的转导。DHCR7 通过降低 7-DHC 浓度和促进 G 蛋白偶联受体 GIPR 的转录，进一步增强了 cAMP 信号通路。总体而言，这些发现表明 DHCR7 通过调节胆固醇合成和 cAMP 信号传导在 BC 侵袭和转移中发挥重要作用。此外，抑制 DHCR7 有望成为抑制 BC 侵袭和转移的可行治疗策略。