Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V6T 1Z4, Canada.
Michael Smith Genome Sciences Center, British Columbia Cancer Agency, Vancouver V5Z 4S6, Canada.
Cancer Biol Med. 2020 May 15;17(2):343-356. doi: 10.20892/j.issn.2095-3941.2019.0261.
Heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone that facilitates collagen maturation. Its role in cancer remains largely unknown. In this study, we investigated the roles of HSP47 in colorectal cancer (CRC) and therapy resistance. Expression of HSP47 in CRC tissues was examined (1) in paired human CRC/adjacent normal tissues, using real time quantitative reverse transcription polymerase chain reaction (qRT-PCR), The Cancer Genome Atlas (TCGA) database, and 22 independent microarray databases (curated CRC). studies on several CRC cell lines (HCT116, RKO and CCL228) with modulated HSP47 expression were conducted to assess cell viability and apoptosis (TUNEL assay and caspase-3/-7) during exposure to chemotherapy. AKT signaling and co-immunoprecipitation studies were performed to examine HSP47 and PHLPP1 interaction. studies using tumor xenografts were conducted to assess the effects of HSP47 modulation on tumor growth and therapy response. HSP47 was upregulated in CRC and was associated with poor prognosis in individuals with CRC. , HSP47 overexpression supported the survival of CRC cells, whereas its knockdown sensitized cells to 5-fluorouracil (5-FU). HSP47 promoted survival by inhibiting apoptosis, enhancing AKT phosphorylation, and decreasing expression of the AKT-specific phosphatase PHLPP1 when cells were exposed to chemotherapy. These effects were partly results of the interaction between HSP47 and PHLPP1, which decreased PHLPP1 stability and led to more persistent AKT activity. , HSP47 supported tumor growth despite 5-FU treatment. HSP47 supports the growth of CRC tumors and suppresses the efficacy of chemotherapy modulation of AKT signaling.
热休克蛋白 47（HSP47）是一种胶原特异性分子伴侣，有助于胶原成熟。其在癌症中的作用在很大程度上尚不清楚。在这项研究中，我们研究了 HSP47 在结直肠癌（CRC）和治疗耐药中的作用。使用实时定量逆转录聚合酶链反应（qRT-PCR）、癌症基因组图谱（TCGA）数据库和 22 个独立的微阵列数据库（精心策划的 CRC），在配对的人 CRC/相邻正常组织中检查了 HSP47 在 CRC 组织中的表达。在暴露于化疗时，对具有调节 HSP47 表达的几种 CRC 细胞系（HCT116、RKO 和 CCL228）进行了细胞活力和细胞凋亡（TUNEL 测定和 caspase-3/-7）研究。进行 AKT 信号转导和共免疫沉淀研究，以检查 HSP47 和 PHLPP1 相互作用。进行了肿瘤异种移植研究，以评估 HSP47 调节对肿瘤生长和治疗反应的影响。HSP47 在 CRC 中上调，并与 CRC 患者的预后不良相关。此外，HSP47 过表达支持 CRC 细胞的存活，而其敲低则使细胞对 5-氟尿嘧啶（5-FU）敏感。当细胞暴露于化疗时，HSP47 通过抑制细胞凋亡、增强 AKT 磷酸化和降低 AKT 特异性磷酸酶 PHLPP1 的表达来促进细胞存活。这些作用部分是 HSP47 和 PHLPP1 之间相互作用的结果，该相互作用降低了 PHLPP1 的稳定性，导致 AKT 活性持续时间更长。此外，HSP47 尽管进行了 5-FU 治疗，但仍支持肿瘤生长。总之，HSP47 支持 CRC 肿瘤的生长，并抑制化疗的疗效，通过调节 AKT 信号。
