Sec23a mediates miR-200c augmented oligometastatic to polymetastatic progression

Abstract

BackgroundCancer treatment is based on tumor staging. Curative intent is only applied to localized tumors. Recent studies show that oligometastatic patients who have limited number of metastases may benefit from metastasis-directed local treatments to achieve long-term survival. However, mechanisms underlying oligometastatic to polymetastatic progression remains elusive.MethodsThe effects of miR-200c and Sec23a on tumor metastasis were verified both in vitro and in vivo. The secretome changes were detected by mass spectrometry.FindingsWe established a pair of homologous lung-metastasis derived oligometastatic and polymetastatic cell lines from human melanoma cancer cell line M14. Using the two cell lines, we have identified Sec23a, a gene target of miR-200c, suppresses miR-200c augmented oligometastatic to polymetastatic progression via its secretome. Firstly, miR-200c over-expression and Sec23a interference accelerated oligometastatic to polymetatic progression. Secondly, Sec23a functions downstream of miR-200c. Thirdly, mass spectrometric analysis of the secretory protein profile suggests that Sec23a-dependent secretome may impact metastatic colonization by modifying tumor microenvironment. Fourthly, the survival analysis using The Cancer Genome Atlas database shows Sec23a as a favorable prognostic marker for skin cutaneous melanoma, supporting the clinical relevance of our findings.InterpretationThe finding that Sec23a is a suppressor of oligometastatic to polymetastatic progression has clinical implications. First, it provides a new theoretical framework for the development of treatments that prevent oligometastasis to polymetastasis. Second, Sec23a may be used as a favorable prognostic marker for the selection of patients with stable oligometastatic disease for oligometastasis-based local therapies of curative intent.FundNational Natural Science Foundations of China.

S100A8 transported by SEC23A inhibits metastatic colonization via autocrine activation of autophagy

“…Transwell migration and invasion assay were conducted as we previously reported 18 . Briefly, 8 μm pore size transwell inserts and Matrigel for invasion assay were purchased from BD.…”

“…Colony formation assay was conducted as we previously reported 18 . Briefly, tumor cells in DMEM containing 2% agar and 10% FBS were plated into 6-well plates and coated with DMEM containing 0.5% agar.…”

“…In the present study, we focus on uncovering mechanisms underlying autophagic regulation of the colonization step of metastasis. We employed a paired of lung-derived oligometastatic cell line (OL) and the homologous polymetastatic cell line (POL) from human melanoma cell line M14 that we previously developed and characterized 18,42 . We have elucidated a new mechanism by which the secretome of tumor cells hinders metastasis through activation of autophagy.…”

Micro RNAs Promoting Growth and Metastasis in Preclinical In Vivo Models of Subcutaneous Melanoma

“…Heat shock proteins, such as DNAJ4 have been shown to be involved in proliferation, differentiation and carcinogenesis (61). miR-200c ( Figure 2) was shown to target SEC 23 homolog A (SEC23A) (62). SEC23A interacts with components involved in anterograde versicle transport from the endoplasmic reticulum to the Golgi apparatus (63).…”

“…Overexpression of miR-200c and SEC23A interference accelerate oligometastatic to polymetastatic progression of human melanoma cell line M14 after tail vein injection (63). The metastasis promoting activity of miR-200 is dependent on selective reprogramming of the secretome by depletion of SEC23A (62,64). As identifed by mass spectrometry, different proteins such as thrombospondin (65), transferrin (66), vitamin D binding protein (67), C-X-C chemokine receptor 4 (CXCR4) (68) and S100 calcium-binding protein A8 (S100A8) (69) may be involved in promoting metastasis by miR-200c.…”