Metformin inhibits melanoma cell metastasis by suppressing the miR-5100/SPINK5/STAT3 axis

Abstract

Melanoma is the most lethal skin cancer characterized by its high metastatic potential. It is urgent to find novel therapy strategies to overcome this feature. Metformin has been confirmed to suppress invasion and migration of various types of cancer. However, additional mechanisms underlying the antimetastatic effect of metformin on melanoma require further investigation. Here, we performed microarray analysis and uncovered an altered mRNA and miRNA expression profile between melanoma and nevus. Luciferase reporter assay confirmed that miR-5100 targets SPINK5 to activate STAT3 phosphorylation. Migration and wound healing assays showed that the miR-5100/SPINK5/STAT3 axis promotes melanoma cell metastasis; the mechanism was proven by initiation of epithelial–mesenchymal transition. Co-immunoprecipitation (Co-IP) further confirmed an indirect interaction between SPINK5 and STAT3. Furthermore, metformin dramatically inhibited miR-5100/SPINK5/STAT3 pathway, and decreased B16-F10 cell metastasis to lung in C57 mouse module. Intriguingly, pretreatment of metformin before melanoma cell injection improved this effect further. These findings exposed the underlying mechanisms of action of metformin and update the use of this drug to prevent metastasis in melanoma.

SPINK5 inhibits esophageal squamous cell carcinoma metastasis via immune activity

“…10 SPINK5 is also reported to be downregulated in melanoma, and its overexpression inhibits the migration and epithelialmesenchymal transition of melanoma cells. 27 SPINK5 is regarded a prostate cancer-related gene and is downregulated by miR-32, which facilitates the proliferation and metaplastic transformation in prostate epithelium and might be related to the prostate cancer progression. 28 In the present study, SPINK5 mRNA downregulation was detected in the tumor tissues compared to the corresponding normal tissues of 196 ESCC patients.…”

Epithelial–mesenchymal transition inhibition by metformin reduces melanoma lung metastasis in a murine model

“…This effect has been associated with the inhibitory action of metformin on the MAPK/ERK pathway, which is overactivated in melanomas due to mutations in BRAF , NRAS , and NF1 and promotes increased cell proliferation and expression of EMT-inducing transcription factors 24 , 25 . Recently Suwei et al, show that metformin effects on EMT are dependent on the miR-5100/SPINK5/STAT3 pathway 26 . SPINK5 is a tumor suppressor protein that regulates EMT on melanoma cells, and when overexpressed inhibits metastasis abilities 26 , 27 .…”

“…Recently Suwei et al, show that metformin effects on EMT are dependent on the miR-5100/SPINK5/STAT3 pathway 26 . SPINK5 is a tumor suppressor protein that regulates EMT on melanoma cells, and when overexpressed inhibits metastasis abilities 26 , 27 . The STAT3 pathway is a known driver stimulator of EMT when phosphorylated at the pY705 site 28 and SPINK5 could inhibit STAT3 phosphorylation.…”

“…The STAT3 pathway is a known driver stimulator of EMT when phosphorylated at the pY705 site 28 and SPINK5 could inhibit STAT3 phosphorylation. The treatment with metformin suppressed miR-5100, which targets SPINK5, and elevated SPINK5 expression, reducing STAT3 phosphorylate 26 .…”

Diabetes and skin cancers: Risk factors, molecular mechanisms and impact on prognosis

“…Metformin has been shown to be an effective antitumor drug in the treatment of a variety of cancers, including melanoma. Metformin has been shown in some cohort studies to inhibit the invasion and migration of various types of cancers[ 99 ] (Table 1 ). Metformin inhibits melanoma cell invasion and metastasis by activating adenosine monophosphate-activated kinase activator, which reduces cancer cell mTOR signaling and protein synthesis.…”