Kong Lingmiao, Xiong Ying, Wang Denian, Huang Luping, Li Min, Feng Zhongxue, Zhou Yue, Zhang Haili, Liu Fei, Xiao Fei, Wei Yong'gang, Zhang Wei
Department of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No. 2222, Frontier Medical Center, Xin Chuan Road, Zhong He Street, Chengdu, 610212, Sichuan, People's Republic of China.
Department of Periodical Press, West China Hospital, Sichuan University, Chengdu, China.
Breast Cancer Res Treat. 2022 Sep;195(2):91-103. doi: 10.1007/s10549-022-06687-0. Epub 2022 Jul 28.
Breast cancer is the most frequently diagnosed cancer and is the leading cause of cancer-associated mortality in women worldwide. Intermedin (IMD, also known as Adrenomedullin 2, ADM2) is an endogenous peptide that belongs to the calcitonin gene-related peptide family and has been reported to play important roles in several types of cancers, including breast cancer. In this study, we sought to investigate how IMD affects the behavior of breast cancer cells, the underlying mechanism of these effects, and whether blockade of IMD has a therapeutic effect against breast cancer.
Transcriptome sequencing (RNA-Seq), cell biological experiments, Western blotting, immunoprecipitation, and animal tumor models were used.
IMD expression was significantly increased in breast cancer samples, and the IMD level was positively correlated with lymph node metastasis and Ki67 expression. Cell biological experiments showed that IMD promoted the anchorage-independent growth, migration, and invasive ability of breast cancer cells. Inhibiting IMD activity with an anti-IMD monoclonal antibody blocked these tumor-promoting effects. In addition, blockade of IMD reduced in situ tumor growth and significantly decreased lung metastasis of 4T1 breast cancer in vivo. IMD induced Src kinase phosphorylation, which triggered the transcription of c-Myc, a major oncoprotein controlling the expression of genes that encode ribosomal components. Our data suggest that IMD is involved in breast cancer cell invasion and metastasis, potentially through increasing ribosome biogenesis and protein translation via the Src/c-Myc signaling pathway.
These results suggest that IMD may be a novel target for the treatment of breast cancer.
乳腺癌是最常被诊断出的癌症，也是全球女性癌症相关死亡的主要原因。中间介质（IMD，也称为肾上腺髓质素2，ADM2）是一种内源性肽，属于降钙素基因相关肽家族，据报道在包括乳腺癌在内的几种癌症中发挥重要作用。在本研究中，我们试图研究IMD如何影响乳腺癌细胞的行为、这些影响的潜在机制，以及阻断IMD是否对乳腺癌具有治疗作用。
采用转录组测序（RNA-Seq）、细胞生物学实验、蛋白质免疫印迹法、免疫沉淀法和动物肿瘤模型。
乳腺癌样本中IMD表达显著增加，IMD水平与淋巴结转移和Ki67表达呈正相关。细胞生物学实验表明，IMD促进乳腺癌细胞的非锚定依赖性生长、迁移和侵袭能力。用抗IMD单克隆抗体抑制IMD活性可阻断这些促肿瘤作用。此外，阻断IMD可减少原位肿瘤生长，并显著降低4T1乳腺癌在体内的肺转移。IMD诱导Src激酶磷酸化，从而触发c-Myc的转录，c-Myc是一种主要的癌蛋白，控制着编码核糖体成分的基因的表达。我们的数据表明，IMD可能通过Src/c-Myc信号通路增加核糖体生物合成和蛋白质翻译，从而参与乳腺癌细胞的侵袭和转移。
这些结果表明，IMD可能是治疗乳腺癌的一个新靶点。
