血行转移限制了结直肠癌（CRC）患者的生存。在这里，我们阐明了 CD44 同工型在此过程中的作用。同工型 3 和 4 主要在 CRC 患者中表达。 CD44 同工型 4 表明预后较差，并与上皮间质转化 (EMT) 和患者氧化磷酸化降低相关；亚型 3 发现了相反的关联。泛 CD44 敲低 (kd) 独立损害原发肿瘤形成并消除 CRC 异种移植物中的远处转移。异种移植肿瘤主要表达临床相关的CD44亚型3和4。两种亚型在坏死、缺氧的肿瘤区域中均增强，但在肺转移瘤中通常不存在。 CD44 kd后，坏死旁区域的肿瘤血管生成增加，伴随着HIF-1α和CEACAM5减少，但E-钙粘蛋白表达增加。线粒体基因和蛋白质以及氧化磷酸化基因均在 pan-CD44 kd 上被诱导。缺氧增加了肿瘤球中 VEGF 的释放，特别是在 CD44 kd 时。异种移植物中影响 CD44 kd 的基因与患者中与 CD44 亚型 4（但不是亚型 3）相关的基因特异性重叠，验证了所用模型的临床相关性，并强调了 CD44 亚型 4 的促进转移作用。本文受保护通过版权。版权所有。

Hematogenous metastasis limits the survival of colorectal cancer (CRC) patients. Here, we illuminated the roles of CD44 isoforms in this process. Isoforms 3 and 4 were predominantly expressed in CRC patients. CD44 isoform 4 indicated poor outcome and correlated with epithelial-mesenchymal transition (EMT) and decreased oxidative phosphorylation in patients; opposite associations were found for isoform 3. Pan-CD44 knockdown (kd) independently impaired primary tumor formation and abrogated distant metastasis in CRC xenografts. The xenograft tumors mainly expressed the clinically relevant CD44 isoforms 3 and 4. Both isoforms were enhanced in the paranecrotic, hypoxic tumor regions but were generally absent in lung metastases. Upon CD44 kd, tumor angiogenesis was increased in the paranecrotic areas, accompanied by reduced HIF-1α and CEACAM5 but increased E-cadherin expression. Mitochondrial genes and proteins were induced upon pan-CD44 kd, as were oxidative phosphorylation genes. Hypoxia increased VEGF release from tumor spheres, particularly upon CD44 kd. Genes affected upon CD44 kd in xenografts specifically overlapped concordantly with genes correlating with CD44 isoform 4 (but not isoform 3) in patients, validating the clinical relevance of the used model and highlighting the metastasis-promoting role of CD44 isoform 4.This article is protected by copyright. All rights reserved.