Tumor-Derived Exosomal piR-hsa-28212 Promotes Lymphatic Metastasis in Breast Cancer.

Area of Science:

• Molecular Oncology
• Cancer Metastasis
• Exosome Biology

Background:

• Lymph node (LN) metastasis is a key prognostic factor in breast cancer (BC).
• BC-derived exosomes mediate intercellular communication, influencing tumor microenvironment and metastasis.
• Mechanisms of exosome-driven LN metastasis in BC require further elucidation.

Purpose of the Study:

• To identify Piwi-interacting RNAs (piRNAs) in serum exosomes associated with BC LN metastasis.
• To investigate the functional role of exosomal piR-hsa-28212 in promoting BC lymph node metastasis.
• To elucidate the molecular mechanisms underlying exosomal piR-hsa-28212-mediated metastasis.

Main Methods:

• Small RNA sequencing of serum exosomes from BC patients.
• In vitro assays (HLEC migration, tube formation) and in vivo metastasis models.
• Luciferase reporter assays, actinomycin D assay, RNA pulldown, RIP, and FISH assays.

Main Results:

• PiR-hsa-28212 was significantly upregulated in serum exosomes of BC patients with LN metastasis.
• Exosomal piR-hsa-28212 promoted HLEC migration, tube formation, lymphangiogenesis, and LN metastasis.
• PiR-hsa-28212 stabilized TBX1 mRNA, upregulating VEGFR3 in HLECs, and stabilized METTL3 in BC cells, increasing VEGFC expression.

Conclusions:

• Exosomal piR-hsa-28212 acts as a crucial mediator in BC lymph node metastasis.
• It functions by enhancing VEGFC/VEGFR3 signaling through interactions with TBX1, METTL3, and downstream targets.
• PiR-hsa-28212 represents a promising therapeutic target for inhibiting BC metastasis.