Department of Ultrasound, The Second Medical Center of Chinese PLA General Hospital, Beijing, China.
Department of Ultrasound, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
Cancer Med. 2020 Jul;9(14):4971-4979. doi: 10.1002/cam4.3130. Epub 2020 May 21.
Breast cancer was the most frequent and the second most deadly cancer in women in 2018 in China; thus, early diagnosis of breast cancer is important. Studies have reported that tissue stiffness promotes cancer progression through increased collagen or fibrosis. Shear wave elastography (SWE) is a technique for measuring tissue stiffness. However, the mechanisms underlying cancer tissue stiffness or fibrosis are not entirely clear. Hypoxia-inducible factor 1 (HIF-1α) is expressed in response to hypoxia and contributes to tumor progression and metastasis. Kindlin-2 is an important co-activator of integrin. We have reported that Kindlin-2 influences breast cancer stiffness and metastasis. In this study, SWE was used to determine the maximum elasticity (E ) of patients before operation or core needle biopsy. The specimens were used for staining. Knockdown, overexpression, co-immunoprecipitation, and immunofluorescence assays were used to explore the relationship between HIF-1α and Kindlin-2. We found that HIF-1α and Kindlin-2 were highly expressed in invasive breast cancer and that the expression levels of HIF-1α and Kindlin-2 were correlated with E . HIF-1α interacts with Kindlin-2. Besides, HIF-1α and Kindlin-2 influence the expression of P4HA1, an important protein in collagen biogenesis through the integrin/FAK pathway. Our study first identified a new mechanism of invasive breast cancer stiffness by linking HIF-1α and Kindlin-2 to collagen biogenesis. Therefore, based on SWE, E could be a physical biomarker of invasive breast cancer for early, noninvasive diagnosis, and HIF-1α and Kindlin-2 could be pathological markers for early diagnosis and targeted therapy.
在中国，2018 年乳腺癌是女性中最常见的也是第二大最致命的癌症；因此，乳腺癌的早期诊断很重要。研究报道组织硬度通过增加胶原蛋白或纤维化促进癌症进展。剪切波弹性成像（SWE）是一种测量组织硬度的技术。然而，癌症组织硬度或纤维化的机制尚不完全清楚。缺氧诱导因子 1（HIF-1α）在缺氧时表达，有助于肿瘤的进展和转移。Kindlin-2 是整合素的重要共激活子。我们已经报道 Kindlin-2 影响乳腺癌的硬度和转移。在这项研究中，使用 SWE 在手术前或芯针活检前确定患者的最大弹性（E）。使用标本进行染色。使用敲低、过表达、共免疫沉淀和免疫荧光测定来探索 HIF-1α 和 Kindlin-2 之间的关系。我们发现 HIF-1α 和 Kindlin-2 在浸润性乳腺癌中高表达，并且 HIF-1α 和 Kindlin-2 的表达水平与 E 相关。HIF-1α 与 Kindlin-2 相互作用。此外，HIF-1α 和 Kindlin-2 通过整合素/FAK 途径影响胶原蛋白生物合成的重要蛋白 P4HA1 的表达。我们的研究首次通过将 HIF-1α 和 Kindlin-2 与胶原蛋白生物合成联系起来，确定了浸润性乳腺癌硬度的新机制。因此，基于 SWE，E 可以作为浸润性乳腺癌的物理生物标志物，用于早期、非侵入性诊断，而 HIF-1α 和 Kindlin-2 可以作为早期诊断和靶向治疗的病理标志物。
