顺铂基化疗是膀胱癌治疗的一线疗法。但是，顺铂诱导了与NF-κB和癌性消瘦相关的肌肉消耗。HOTAIR是一个致癌性长链非编码RNA（lncRNA），在不同癌症中促进癌症进展。HOTAIR与NF-κB之间的相互作用已有文献证明。前胸腺素α（ProT）在癌症进展和炎症中起重要作用。然而，HOTAIR、ProT和顺铂诱导的癌性消瘦之间的潜在联系尚未探索。在这里，我们调查了HOTAIR在顺铂诱导的癌性消瘦中的贡献，并分析了涉及表皮生长因子受体（EGFR）、ProT、NF-κB和HOTAIR的潜在信号级联。使用RT-qPCR检测了膀胱癌患者和膀胱癌细胞系的肿瘤组织中ProT和HOTAIR转录本的表达及其相关性。然后，通过免疫印迹分析人膀胱癌细胞中的磷酸化EGFR、EGFR、磷酸化NF-κB和NF-κB水平，治疗顺铂。还通过RT-qPCR评估顺铂处理的细胞中HOTAIR的表达。利用药物抑制剂和过表达和敲低方法解密信号通路。小鼠C2C12肌细胞生长（in vitro）用作肌肉萎缩模型。同种小鼠MBT-2膀胱肿瘤用于研究小鼠Hotair在顺铂诱导的癌性消瘦中的作用。ProT和HOTAIR的表达在膀胱肿瘤中高于正常相邻组织。在临床膀胱癌肿瘤和膀胱癌细胞系中，ProT和HOTAIR表达呈正相关。顺铂治疗增加了膀胱癌细胞中EGFR和NF-κB的活化，并上调了ProT和HOTAIR的表达。ProT过表达增加，ProT敲低减少HOTAIR的表达。值得注意的是，EGFR抑制剂或ProT敲低消除了顺铂诱导的HOTAIR上调。NF-κB抑制剂降低了ProT诱导的HOTAIR过表达。HOTAIR过表达增强，而敲低减少了细胞增殖、癌症相关的促炎性细胞因子表达和肌肉萎缩。在承受顺铂治疗的Hotair敲低膀胱肿瘤的小鼠中，消瘦相关症状得到缓解。我们第一次证明了HOTAIR的重要作用，并确定了EGFR-ProT-NF-κB-HOTAIR信号轴在顺铂诱导的膀胱癌和可能的其他癌症中的缓解中的参与。我们的研究结果为该疾病提供了治疗靶点。 © 2022. 作者（S）。

Cisplatin-based chemotherapy is the first line of treatment for bladder cancer. However, cisplatin induces muscle wasting associated with NF-κB and cancer cachexia. HOTAIR, an oncogenic long non-coding RNA (lncRNA), promotes cancer progression in different cancers. Crosstalk between HOTAIR and NF-κB is documented. Prothymosin α (ProT) plays important roles in cancer progression and inflammation. However, the potential link between HOTAIR, ProT, and cisplatin-induced cancer cachexia remains unexplored. Here, we investigated the contribution of HOTAIR in cisplatin-induced cancer cachexia and dissected the potential signaling cascade involving the epidermal growth factor receptor (EGFR), ProT, NF-κB, and HOTAIR.Expression of ProT and HOTAIR transcripts and their correlations in tumor tissues of bladder cancer patients and bladder cancer cell lines were determined by RT-qPCR. Next, levels of phospho-EGFR, EGFR, phospho-NF-κB, and NF-κB were examined by immunoblot analysis in human bladder cancer cells treated with cisplatin. Expression of HOTAIR in cisplatin-treated cells was also assessed by RT-qPCR. Pharmacological inhibitors and overexpression and knockdown approaches were exploited to decipher the signaling pathway. The murine C2C12 myoblasts were used as an in vitro muscle atrophy model. The syngeneic murine MBT-2 bladder tumor was used to investigate the role of mouse Hotair in cisplatin-induced cancer cachexia.Expression of ProT and HOTAIR was higher in bladder tumors than in normal adjacent tissues. There were positive correlations between ProT and HOTAIR expression in clinical bladder tumors and bladder cancer cell lines. Cisplatin treatment increased EGFR and NF-κB activation and upregulated ProT and HOTAIR expression in bladder cancer cells. ProT overexpression increased, whereas ProT knockdown decreased, HOTAIR expression. Notably, cisplatin-induced HOTAIR upregulation was abrogated by EGFR inhibitors or ProT knockdown. ProT-induced HOTAIR overexpression was diminished by NF-κB inhibitors. HOTAIR overexpression enhanced, whereas its knockdown reduced, cell proliferation, cachexia-associated pro-inflammatory cytokine expression, and muscle atrophy. Cachexia-associated symptoms were ameliorated in mice bearing Hotair-knockdown bladder tumors undergoing cisplatin treatment.We demonstrate for the first time a critical role for HOTAIR and identify the involvement of the EGFR-ProT-NF-κB-HOTAIR signaling axis in cisplatin-induced cachexia in bladder cancer and likely other cancers. Our findings also provide therapeutic targets for this disease.© 2022. The Author(s).