人乳头瘤病毒 (HPV) 是导致恶性肿瘤的主要原因，约占全世界人类癌症的 5%，其中包括大多数宫颈癌病例以及越来越多的肛门生殖器癌和口腔癌。主要的 HPV 病毒癌基因 E6 和 E7 操纵许多促进细胞增殖和存活的宿主细胞途径，使受感染的细胞易于发生恶性转化。尽管已有高效疫苗，但仍然没有针对 HPV 的特异性抗病毒疗法或 HPV 相关癌症的治疗方法。因此，更好地了解病毒与宿主的相互作用可能有助于识别新的治疗靶点。在这里，我们证明肌动蛋白结合蛋白 LASP1 在宫颈癌中表达上调，并且与较差的总体生存率显着相关。在 HPV 阳性宫颈癌中，LASP1 缺失在体外显着抑制致癌表型，而对 HPV 阴性宫颈癌细胞影响最小。此外，我们证明 LASP1 SH3 结构域对于这些细胞中 LASP1 介导的致癌性至关重要。从机制上讲，我们表明 HPV E7 通过抑制 miR-203 的表达在转录后水平调节 LASP1，而 miR-203 通过与其 3'UTR 结合来负向调节 LASP1 mRNA 水平。最后，我们证明 LASP1 表达是 HPV 阳性宫颈癌细胞在体内致瘤模型中生长所必需的。总之，这些数据表明 HPV 诱导 LASP1 表达，促进宫颈癌的增殖和存活，从而确定这些癌症的潜在治疗靶点。© 2024。作者。

Human papillomaviruses (HPV) are a major cause of malignancy, contributing to ~5% of all human cancers worldwide, including most cervical cancer cases and a growing number of anogenital and oral cancers. The major HPV viral oncogenes, E6 and E7, manipulate many host cellular pathways that promote cell proliferation and survival, predisposing infected cells to malignant transformation. Despite the availability of highly effective vaccines, there are still no specific anti-viral therapies targeting HPV or treatments for HPV-associated cancers. As such, a better understanding of viral-host interactions may allow the identification of novel therapeutic targets. Here, we demonstrate that the actin-binding protein LASP1 is upregulated in cervical cancer and significantly correlates with a poorer overall survival. In HPV positive cervical cancer, LASP1 depletion significantly inhibited the oncogenic phenotype in vitro, whilst having minimal effects in HPV negative cervical cancer cells. Furthermore, we demonstrate that the LASP1 SH3 domain is essential for LASP1-mediated oncogenicity in these cells. Mechanistically, we show that HPV E7 regulates LASP1 at the post-transcriptional level by repressing the expression of miR-203, which negatively regulates LASP1 mRNA levels by binding to its 3'UTR. Finally, we demonstrate that LASP1 expression is required for the growth of HPV positive cervical cancer cells in an in vivo tumourigenicity model. Together, these data demonstrate that HPV induces LASP1 expression to promote proliferation and survival in cervical cancer, thus identifying a potential therapeutic target in these cancers.© 2024. The Author(s).