Department of Orthopedic Surgery, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China.
Department of Orthopedic Surgery, Sarcoma Biology Laboratory, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
J Orthop Res. 2020 Nov;38(11):2362-2372. doi: 10.1002/jor.24848. Epub 2020 Sep 19.
Leucine-rich repeat containing 15 (LRRC15) is a member of the leucine-rich repeat superfamily that is overexpressed in various cancers and associated with higher tumor grade and aggression. Despite its known tumorigenicity, its roles within osteosarcoma are unknown, prompting us to evaluate its expression and clinical significance within this rare yet aggressive cancer. Western blots showed differential expression of LRRC15 in the osteosarcoma cell lines MNNG/HOS, KHOS, 143B, MG63, Saos-2, and U2OS. We additionally validated this positive expression, as well as sublocalization to the cell membrane, with immunofluorescence. A tissue microarray constructed from 69 osteosarcoma patient tissues was immunohistochemically stained for LRRC15 expression, stratified, and used for clinicopathological analysis. Publicly available databases on LRRC15 expression, including RNA sequencing data from the Therapeutically Applicable Research to Generate Effective Treatments on Osteosarcoma (TARGET-OS) and the Gene Expression database of Normal and Tumor tissues 2 (GENT2) were also analyzed. We found 63 of the 69 (91.3%) patient tissues exhibited some degree of LRRC15 immunostaining, including no staining (6 of 69, 8.7%), 1+ staining (12 of 69, 17.4%), 2+ staining (25 of 69, 36.2%), and 3+ staining (26 of 69, 37.7%). The patients with osteosarcomas having elevated LRRC15 expression demonstrated comparatively increased metastasis, chemoresistance, and shorter 5-year survival rates. Our analysis of the TARGET-OS and GENT2 databases also showed increased LRRC15 gene expression in osteosarcoma. Taken together, our study supports LRRC15 as a prognostic biomarker and emerging therapeutic target in osteosarcoma.
富含亮氨酸重复序列 15（LRRC15）是亮氨酸重复超家族的成员，在各种癌症中过度表达，并与更高的肿瘤分级和侵袭性相关。尽管其已知的致瘤性，但在骨肉瘤中的作用尚不清楚，促使我们评估其在这种罕见但侵袭性癌症中的表达和临床意义。Western blot 显示 LRRC15 在骨肉瘤细胞系 MNNG/HOS、KHOS、143B、MG63、Saos-2 和 U2OS 中的表达存在差异。我们还通过免疫荧光验证了这种阳性表达，以及细胞膜的亚定位。从 69 例骨肉瘤患者组织构建的组织微阵列用 LRRC15 表达进行免疫组织化学染色，分层，并用于临床病理分析。还分析了 LRRC15 表达的公共数据库，包括来自治疗性应用研究以生成有效的骨肉瘤治疗（TARGET-OS）的 RNA 测序数据和正常和肿瘤组织 2（GENT2）的基因表达数据库。我们发现 69 例患者组织中有 63 例（91.3%）表现出某种程度的 LRRC15 免疫染色，包括无染色（6/69，8.7%）、1+染色（12/69，17.4%）、2+染色（25/69，36.2%）和 3+染色（26/69，37.7%）。LRRC15 表达升高的骨肉瘤患者表现出比较高的转移、化疗耐药性和较短的 5 年生存率。我们对 TARGET-OS 和 GENT2 数据库的分析也表明骨肉瘤中 LRRC15 基因表达增加。总之，我们的研究支持 LRRC15 作为骨肉瘤的预后生物标志物和新兴治疗靶点。
