Third Department of Hepatic Surgery, Third Affiliated Hospital, Naval Medical University, Shanghai 200438, China.
Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai 200438, China.
Int J Biol Sci. 2023 Jan 22;19(4):1009-1023. doi: 10.7150/ijbs.73570. eCollection 2023.
Bones are categorized as the second most prevalent location of extra-hepatic metastasis in Hepatocellular Carcinoma (HCC), which is linked to an extremely poor prognosis due to limited therapeutic options. N-methyladenosine (mA) is a prominent modification involved in HCC, but the exact mechanisms on how mA modifications induce HCC bone metastases (BM) remain unclear. The key modulators responsible for the abundant mA RNA modification-induced HCC BM was found to be the and . The expression of Anillin actin-binding protein () was dramatically higher in HCC with BM tissues, and its messenger RNA (mRNA) stability was enhanced via mA epitranscriptomic regulation by and . High and expression along with nuclear protein was clinically correlated with BM in HCC patients. Furthermore, HCC BM was attributed to over-expression of nuclear forming a transcriptional complex with which enhanced transcriptional activity to activate the mTORC1 pathway, therefore increased the expression of and disproportionated expression in bone microenvironment leading to malignant neoplasms invade bone tissue. In addition, inhibition of mA modification by DZNeP attenuated HCC BM. This data provides meaningful understanding of the modulation and association of mA epitranscriptomic-regulated BM in HCC, and moreover, defines potentially valuable therapeutic targets.
骨骼是肝癌（HCC）肝外转移的第二大常见部位，由于治疗选择有限，预后极差。N6-甲基腺苷（m6A）是 HCC 中一种重要的修饰物，但 mA 修饰如何诱导 HCC 骨转移（BM）的确切机制尚不清楚。研究发现， 和 是导致富含 mA RNA 修饰诱导 HCC BM 的关键调节剂。在有 BM 组织的 HCC 中，Anillin 肌动蛋白结合蛋白（ ）的表达显著升高，其信使 RNA（mRNA）稳定性通过 和 对 mA 转录后修饰的调节得到增强。高 和 表达以及核 蛋白与 HCC 患者的 BM 具有临床相关性。此外，HCC BM 归因于核 表达增加，与 形成转录复合物，增强 转录活性，激活 mTORC1 途径，从而增加 和 在骨微环境中的表达，导致恶性肿瘤侵犯骨组织。此外，通过 DZNeP 抑制 mA 修饰可减轻 HCC BM。这些数据为理解 mA 转录后修饰调控 HCC BM 提供了有意义的认识，并确定了潜在有价值的治疗靶点。
