Roles of Hsp47 in breast cancer progression

Hsp47 在乳腺癌进展中的作用

• 批准号: 9310552
• 负责人: Ren Xu
• 金额: $ 34.43万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-03 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310552
• 关键词: Adhesions; Adjuvant Therapy; Aftercare; Binding; Biology; Blood Circulation; Blood Platelets; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Epithelial Cells; Cancer Relapse; Cell Survival; Cells; Clinical; Coculture Techniques; Collagen; Collagen Receptors; Deposition; Development; Disseminated Malignant Neoplasm; Distal; Distant; Early Diagnosis; Epithelial; Event; Extracellular Matrix; Extracellular Matrix Proteins; Extravasation; Gene Silencing; Genetic Transcription; Growth; Human; Incidence; Investigation; Knowledge; Lung; Mesenchymal; Metastatic breast cancer; Microfluidics; Migration Assay; Modeling; Molecular; Molecular Chaperones; Mus; Neoplasm Metastasis; Oncogenes; Organ; Pathologist; Pathway interactions; Phenotype; Platelet Activation; Positioning Attribute; Production; Prognostic Marker; Property; Proteins; Proteomics; Recruitment Activity; Regulation; Relapse; Research; Role; Signal Transduction; Site; Stromal Cells; System; Techniques; Testing; Tissue Microarray; Tumor Initiators; Tumor Tissue; Up-Regulation; Xenograft Model; base; cancer cell; carcinogenesis; chemotherapeutic agent; chemotherapy; discoidin domain receptor 2; discoidin receptor; experimental study; imaging system; in vivo; loss of function; malignant breast neoplasm; multidisciplinary; nano; novel; outcome forecast; protein expression; receptor; self-renewal; stemness; therapeutic target; three dimensional cell culture; triple-negative invasive breast carcinoma; tumor growth; tumor microenvironment; tumor progression

Despite recent advance in early diagnosis and adjuvant therapy, treatment of triple negative breast cancer (TNBC) remains a significant challenge because of the high incidence of metastasis and relapse after treatment. Signaling from extracellular matrix (ECM), an essential component of the tumor microenvironment, is required for TNBC progression and metastasis. However, it is not known how cancer cell-deposited ECM proteins and ECM signaling in cancer cells are regulated and promote TNBC metastasis/relapse. We recently identified Hsp47 as a hub of the ECM transcription network. Hsp47 is a molecular chaperon that regulates secretion and deposition of ECM proteins. Increased Hsp47 expression has been detected in TNBC and is associated with cancer metastasis. Silencing Hsp47 restrains the aggressive phenotype of TNBC cells in 3D culture and inhibits tumor growth and lung colonization in the xenograft model, indicating that increased Hsp47 expression is crucial for the TNBC progression. EMT promotes cancer progression by enhancing cancer cell dissemination and endowing cancer cells with “stemness” properties that favor successful colonization in distant organs and contribute to chemoresistance. Platelet adhesion and activation are required for cancer cell colonization at the distal sites. We found that silencing Hsp47 in metastatic breast cancer cells significantly reduced platelet adhesion. These results suggest that Hsp47 promotes TNBC metastasis/relapse by inducing EMT and platelet recruitment. In Aim 1, we will investigate the molecular mechanism by which Hsp47 regulates EMT and stemness properties. In Aim 2, we will determine the cellular mechanism by which Hsp47 promotes colonization of breast cancer cells at the secondary organs. In Aim 3, we will define the roles of Hsp47 in promoting cancer metastasis and chemoresistance in TNBC. This investigation will change the current concept of ECM microenvironment in cancer metastasis by revealing new roles of cancer cell-derived collagen in inducing cancer cell-platelet interaction and metastasis. Characterization of Hsp47 as a hub of collagen/DDR2 signaling will identify a novel pathway to inhibit TNBC progression and chemoresistance.

尽管近年来在早期诊断和辅助治疗方面取得了进展， 癌症（TNBC）仍然是一个重大的挑战，因为转移和复发的高发病率后， 治疗细胞外基质（ECM）是肿瘤微环境的重要组成部分， 是TNBC进展和转移所必需的。然而，目前尚不清楚癌细胞沉积的ECM是如何形成的。 调节癌细胞中的蛋白质和ECM信号传导并促进TNBC转移/复发。我们最近 将Hsp 47确定为ECM转录网络的枢纽。Hsp 47是一种调节蛋白质的分子伴侣 ECM蛋白的分泌和沉积。已在TNBC中检测到增加的Hsp 47表达， 与癌症转移有关。沉默Hsp 47在3D中抑制TNBC细胞的侵袭性表型 在异种移植模型中，Hsp 47表达增加并抑制肿瘤生长和肺定殖，表明Hsp 47表达增加与肿瘤生长和肺定殖有关。 表达对于TNBC进展至关重要。EMT通过增强癌细胞增殖促进癌症进展 扩散和赋予癌细胞“干性”特性，有利于成功的殖民化， 远距离器官，并有助于耐药性。血小板粘附和活化是癌细胞增殖和转移的必要条件。 在远端部位定植。我们发现，在转移性乳腺癌细胞中沉默Hsp 47， 减少血小板粘附。这些结果表明，Hsp 47通过诱导TNBC转移/复发来促进TNBC转移/复发。 急诊急救和血小板募集。在目的1中，我们将研究Hsp 47调节细胞凋亡的分子机制。 EMT和干性特性。在目标2中，我们将确定Hsp 47促进细胞凋亡的细胞机制。 乳腺癌细胞在次级器官的定植。在目标3中，我们将定义Hsp 47在以下方面的作用： 促进TNBC中的癌症转移和化学抗性。这项调查将改变目前 通过揭示癌细胞源性胶原蛋白的新作用来阐明癌转移中ECM微环境的概念 诱导癌细胞-血小板相互作用和转移。热休克蛋白47作为一个枢纽的表征 胶原/DDR2信号传导将鉴定抑制TNBC进展和化学抗性的新途径。