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

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.

Clinical application of apatinib in the treatment of advanced bone and soft tissue sar-coma / 中国肿瘤临床

To observe the efficacy and safety of apatinib in the treatment of advanced bone and soft tissue sarcoma, and to analyze the possible related factors affecting the progression-free survival (PFS) of patients. Methods: Twenty-one patients with ad-vanced bone and soft tissue sarcoma admitted to the Department of Orthopaedics, Yunnan Cancer Hospital from June 2017 to Sep-tember 2018, were treated with apatinib tablets. The main efficacy index was progression free survival (PFS), and the secondary effica-cy index was overall survival (OS). Clinical efficacy was evaluated according to response evaluation criteria in solid tumors (RECIST) 1.1, and overall response rate (ORR), disease control rate (DCR), and safety were olserved according to the National Cancer Institute (NCI) 4.0 standard. Results: All of the 21 patients were followed up. At the last follow-up time point, March 31st, 2019, there were no CR, 2 patients (9.5%) with PR, 7 patients with SD (33.3%), and 12 patients with PD (57.1%). The ORR was 9.5%, the DCR was 42.8%, the medi-an PFS was 8 months, and the median OS was 14 months. The patient's gender, age, ECOG score, tissue source, surgery, or chemother-apy had no statistically significant effect on PFS (P>0.05). Only the history of radiotherapy before taking apatinib was a factor for pa-tients with PFS. The effect was statistically significant (P<0.05), and patients with a history of radiotherapy had a lower PFS than pa-tients without a history of radiotherapy. The adverse reactions of gradeⅢand above had hand-foot syndrome (14.3%), pneumotho-rax (14.3%) and anemia (4.8%). Conclusions: Apatinib has a certain effect for advanced bone and soft tissue sarcoma. The adverse re-actions are generally predictable, controllable and reversible. Apatinib can be a choice for patients with advanced bone and soft tissue sarcoma with good treatment adherence and no other treatment options.

NLK functions to maintain proliferation and stemness of NSCLC and is a target of metformin.

OBJECTIVE: Nemo-like kinase (NLK) is an evolutionarily conserved serine/threonine kinase that regulates the activity of a wide range of signal transduction pathways. Metformin, an oral antidiabetic drug, is used for cancer prevention. However, the significance and underlying mechanism of NLK and metformin in oncogenesis has not been fully elucidated. Here, we investigate a novel role of NLK and metformin in human non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: NLK expression was analyzed in 121 NSCLCs and 92 normal lung tissue samples from benign pulmonary disease. Lentivirus vectors with NLK-shRNA were used to examine the effect of NLK on cell proliferation and tumorigenesis in vitro. Then, tumor xenograft mouse models revealed that NLK knockdown cells had a reduced ability for tumor formation compared with the control group in vivo. Multiple cell cycle regulator expression patterns induced by NLK silencing were examined by western blots in A549 cells. We also employed metformin to study its anti-cancer effects and mechanisms. Cancer stem cell property was checked by tumor sphere formation and markers including CD133, Nanog, c-Myc, and KLF4. RESULTS: Immunohistochemical (IHC) analysis revealed that NLK expression was up-regulated in NSCLC cases (p < 0.001) and correlated with tumor T stage (p < 0.05). Silencing of NLK suppressed cell proliferation and tumorigenicity significantly in vitro and in vivo, which might be modulated by JUN family proteins. Furthermore, metformin selectively inhibits NLK expression and proliferation in NSCLC cells, but not immortalized noncancerous lung bronchial epithelial cells. In addition, both NLK knockdown and metformin treatment reduced the tumor sphere formation capacity and percentage of CD133+ cells. Accordingly, the expression level of stem cell markers (Nanog, c-Myc, and KLF4) were decreased significantly [corrected]. CONCLUSION: NLK is critical for cancer cell cycle progression, and tumorigenesis in NSCLC, NLK knockdown, and metformin treatment inhibit cancer cell proliferation and stemness. Metformin inhibits NLK expression and might be a potential treatment strategy for NSCLC.