2. Academic Validation
  3. PITX1 suppresses osteosarcoma metastasis through exosomal LINC00662-mediated M2 macrophage polarization

PITX1 suppresses osteosarcoma metastasis through exosomal LINC00662-mediated M2 macrophage polarization

  • Clin Exp Metastasis. 2022 Nov 5. doi: 10.1007/s10585-022-10192-5.
Ying Zhang 1,  Yelong Chen 2,  Chuangzhen Chen 3,  Huancheng Guo 2,  Chunbin Zhou 2,  Hu Wang 2,  Zhaoyong Liu 4
Affiliations

Affiliations

  • 1 Department of Radiotherapy, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, 515041, Guangdong, China. [email protected].
  • 2 Department of Orthopaedics, First Affiliated Hospital of Shantou University Medical College, No.57 Changping Road, Shantou, 515041, Guangdong, China.
  • 3 Department of Radiotherapy, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, 515041, Guangdong, China.
  • 4 Department of Orthopaedics, First Affiliated Hospital of Shantou University Medical College, No.57 Changping Road, Shantou, 515041, Guangdong, China. [email protected].
PMID: 36334221 DOI: 10.1007/s10585-022-10192-5
Abstract

Paired-like homeodomain transcription factor 1 (PITX1) is frequently downregulated in cancers, including osteosarcoma (OS). However, its role in OS remains unknown. Therefore, we aimed to explore the functions and potential mechanisms of PITX1 in OS malignant progression. Elevated PITX1 suppressed OS cell proliferation and migration, based on transwell, proliferation, and colony formation assays. Pathway enrichment analysis of differentially-expressed genes between PITX1-overexpressing and control OS cells indicated that PITX1 expression was associated with the FAK/Src and PI3K/Akt signaling pathways. Mechanistically, ubiquitination assays and rescue experiments showed that PITX1 interacted with transcription factor STAT3, leading to decreased STAT3 transcriptional activity, which repressed the expression of LINC00662. Specific knockdown of LINC00662 reduced the tumor growth and invasion of OS cells induced by downregulated PITX1. Moreover, exosomal LINC00662, derived from PITX1 knockdown OS cell lines activated M2 macrophages in cell co-culture assays. M2 macrophage secreted several cytokines, among which CCL22 was found to cause OS cell EMT. Collectively, our data indicate that PITX1 suppresses OS cell proliferation and metastasis by downregulating LINC00662. Moreover, LINC00662 can be packaged into OS cell-derived exosomes to mediate M2 macrophage polarization to promote OS metastasis via CCL22.

Keywords

CCL22; LINC00662; M2 macrophages; Osteosarcoma; PITX1.

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