Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima 734‑8551, Japan.
Department of Endoscopy and Medicine, Hiroshima University, Hiroshima 734‑8551, Japan.
Oncol Rep. 2021 Jun;45(6). doi: 10.3892/or.2021.8055. Epub 2021 Apr 28.
Tumor‑stroma interactions serve a crucial role in the development of colorectal cancer (CRC), in which secreted protein acidic and rich in cysteine (SPARC) has been implicated. Due to interactions between cancer and stromal cells [mesenchymal stem cells (MSCs)], SPARC gene expression is markedly upregulated in CRC cells. The present study investigated the role of SPARC in CRC development and its potential as a biomarker. Specifically, the present study examined the association between SPARC expression and clinicopathological characteristics in 42 cases of CRC. SPARC expression in cancer cells was associated with T grade, N grade (TNM classification), stage and poor prognosis. Furthermore, the area of fibroblast‑activating protein‑positive staining around the cancer cells was increased in SPARC‑positive compared with SPARC‑negative cases. Proliferation and wound healing assays in SPARC‑silenced KM12SM cells [short hairpin RNA SPARC (shSPARC)], the reduced SPARC expression of which was demonstrated by reverse transcription‑quantitative PCR, revealed that the proliferative and migratory capacity of shSPARC cells did not differ from that of wild‑type (WT) cells. However, it was markedly reduced when co‑cultured with MSCs. Furthermore, , immunohistological analysis and RNA sequencing were conducted in an orthotopic implanted mouse model. Tumor growth and lymph node metastasis were markedly suppressed in shSPARC‑transplanted tumors compared with WT‑transplanted tumors, with a more marked suppression observed following shSPARC co‑transplantation with MSCs. Immunohistological examination further revealed that the stromal reaction and epithelial‑mesenchymal transition (EMT) were markedly suppressed in tumors co‑transplanted with shSPARC and MSCs, and these results were consistent with RNA sequencing using RNA extracted from orthotopic tumors. Overall, these results suggested that SPARC expression in CRC cells is dependent on the interaction between cancer cells and stromal cells to induce EMT and promote stromal formation in the tumor microenvironment, suggesting its suitability as a novel target molecule for CRC treatment.
肿瘤-基质相互作用在结直肠癌（CRC）的发展中起着至关重要的作用，其中富含半胱氨酸的酸性分泌蛋白（SPARC）已被牵涉其中。由于癌症细胞与基质细胞[间充质干细胞（MSCs）]之间的相互作用，SPARC 基因在 CRC 细胞中表达明显上调。本研究探讨了 SPARC 在 CRC 发展中的作用及其作为生物标志物的潜力。具体而言，本研究检查了 SPARC 表达与 42 例 CRC 患者的临床病理特征之间的关联。癌细胞中 SPARC 的表达与 T 分级、N 分级（TNM 分类）、分期和预后不良相关。此外，与 SPARC 阴性病例相比，SPARC 阳性病例中癌细胞周围成纤维细胞激活蛋白阳性染色的面积增加。在 SPARC 沉默的 KM12SM 细胞[短发夹 RNA SPARC（shSPARC）]中转录定量 PCR 显示 SPARC 表达减少的增殖和伤口愈合实验中，shSPARC 细胞的增殖和迁移能力与 WT 细胞没有差异。然而，当与 MSC 共培养时，其能力显著降低。此外，在原位植入的小鼠模型中进行了免疫组织化学分析和 RNA 测序。与 WT 移植瘤相比，shSPARC 移植瘤的肿瘤生长和淋巴结转移明显受到抑制，当与 MSC 共移植 shSPARC 时抑制作用更为明显。免疫组织化学检查进一步显示，共移植 shSPARC 和 MSCs 的肿瘤中基质反应和上皮-间充质转化（EMT）明显受到抑制，这些结果与从原位肿瘤中提取的 RNA 进行的 RNA 测序结果一致。总的来说，这些结果表明，CRC 细胞中的 SPARC 表达依赖于癌细胞与基质细胞之间的相互作用，从而诱导 EMT 并促进肿瘤微环境中的基质形成，表明其适合作为 CRC 治疗的新型靶分子。
