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.

尽管最近在早期诊断和辅助治疗方面取得了进展，但三阴乳房的治疗 癌症(TNBC)仍然是一个巨大的挑战，因为转移和复发的发生率很高 治疗。来自细胞外基质(ECM)的信号，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如何沉积细胞外基质。 癌细胞中的蛋白质和ECM信号受到调控，并促进TNBC转移/复发。我们最近 确定Hsp47是ECM转录网络的枢纽。Hsp47是一种分子伴侣，调节 细胞外基质蛋白的分泌和沉积。在TNBC和IS中检测到Hsp47表达增加 与癌症转移有关。沉默Hsp47在3D中抑制TNBC细胞的侵袭性表型 在异种移植模型中培养并抑制肿瘤生长和肺定植，表明增加了Hsp47 表达对TNBC的进展至关重要。EMT通过增强癌细胞促进肿瘤进展 传播并赋予癌细胞“干性”特性，从而有利于在 远隔器官并导致化疗耐药。癌细胞需要血小板黏附和激活 在远端地点的殖民。我们发现，显著沉默转移性乳腺癌细胞中的Hsp47 减少了血小板的粘附性。这些结果表明，Hsp47通过诱导TnBC转移/复发 EMT和血小板募集。在目标1中，我们将研究hsp47调控的分子机制。 EMT和茎的特性。在目标2中，我们将确定Hsp47促进的细胞机制 乳腺癌细胞在次级器官的定植。在目标3中，我们将定义Hsp47在 促进TNBC的肿瘤转移和化疗耐药。这项调查将改变目前的 肿瘤细胞源性胶原的新作用揭示细胞外基质微环境在肿瘤转移中的作用 在诱导癌细胞-血小板相互作用和转移中的作用。Hsp47作为HSP47基因枢纽的特性 胶原蛋白/DDR2信号通路将确定一条新的抑制TNBC进展和化疗耐药的途径。