LIS1 interacts with CLIP170 to promote tumor growth and metastasis via the Cdc42 signaling pathway in salivary gland adenoid cystic carcinoma

Abstract

Salivary gland adenoid cystic carcinoma (SACC) is one of the most common malignant tumors, with high aggressive potential in the oral and maxillofacial regions. Lissencephaly 1 (LIS1) is a microtubule-organizing center-associated protein that regulates the polymerization and stability of microtubules by mediating the motor function of dynein. Recent studies have suggested that LIS1 plays a potential role in the malignant development of tumors, such as in mitosis and migration. However, the role of LIS1 in SACC development and its related molecular mechanisms remain unclear. Thus, the effects of LIS1 on the proliferation, apoptosis, invasion and metastasis of SACC were studied, in vivo and in vitro . The results of immunohistochemical staining showed that LIS1 was highly expressed in SACC tissues, and its expression level was associated with malignant progression. In vitro , the results of CCK-8, TUNEL, wound healing and Transwell assays demonstrated that LIS1 promotes proliferation, inhibits apoptosis, and enhances the migration and invasion of SACC-LM cells. In vivo , knockdown of LIS1 effectively suppressed the growth of subcutaneous tumors in a mouse xenograft and distant metastasis of tumor cells in the metastasis model. The co-immunoprecipitation, immunofluorescence and western blot results also revealed that LIS1 binds to cytoplasmic linker protein 170 (CLIP170) to form a protein complex (LIS1/CLIP170), which activates the cell division control protein 42 homolog (Cdc42) signaling pathway to modulate the proliferation and anti-apoptosis of tumor cells, and enhanced invasion and metastasis by regulating the formation of invadopodia and the expression of MMPs in SACC-LM cells. Therefore, the present study demonstrated that LIS1 is a cancer promoter in SACC, and the molecular mechanism of the LIS1/CLIP170/Cdc42 signaling pathway is involved in the malignant progression, which offers a promising strategy for targeted therapy of SACC.

TAMs-derived exosomal Meg8 promotes the EMT and metastasis of SACC by regulating EGFR through sponge absorption of miR-148a-3p

“…SACC has a high rate of distant metastasis, which can reach as high as 40% [19]. SACC is inherently resistant to systemic chemotherapy and radiotherapy [20]. The treatment approaches of SACC metastasis are still limited and the prognosis of SACC is pessimistic [21].…”

The Epigenesis of Salivary Glands Carcinoma: From Field Cancerization to Carcinogenesis

“…In adenoid cystic carcinoma, Lissencephaly 1 (L1S1) regulates the invadopodia formation and has been shown to associate with matrix metalloproteinases (MMPs) expression. Lissencephaly L1S1 is a microtubule associated protein which regulates the microtubules stability, and it can mitigate the metastatic potential of ACC through the invadopodia formation and ECM degradation [ 129 ]. Also, integrin linked kinase (ILK), play important role in ECM interactions, with presence of other cofactors such as growth factors and integrin, which regulates cells differentiation, migration and apoptosis.…”