Objective:To explore the relationship between carotid atherosclerosis (CAS) and bone metabolism marker osteocalcin (OC) in patients with type 2 diabetes (T2DM).Methods:A total of 100 patients with T2DM admitted to Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University) from January 2018 to August 2018 were selected as study subjects, and the carotid intima-media thickness (IMT) was detected.The patients were divided into CAS group and normal carotid IMT group (NC group), with 50 cases in each group.The levels of OC, fasting plasma glucose(FPG), fasting insulin(FINS), glycosylated hemoglobin(HbA1c), total cholesterol (TC), triglyceride (TG), high density lipoprotein(HDL-C), low density lipoprotein (LDL-C), insulin resistance index (HOMA-IR) were compared between the two groups.Results:The OC level of the CAS group[(11.86±4.46)ng/mL] was significantly lower than that of the NC group[(23.94±4.52)ng/mL] ( t=-9.640, P=0.001). The LDL-C level of the CAS group[(2.89±0.82)mmol/L] was significantly higher than that of the NC group[(2.55±1.16)mmol/L]( t=2.03, P=0.049). Pearson correlation analysis showed that IMT was positively correlated with age, LDL-C, HbA1c ( r=0.285, 0.190, 0.173; P=0.000, 0.020, 0.035), and negatively correlated with OC ( r=-0.603, P=0.000). Conclusion:CAS in patients with T2DM is closely related to OC, and the reduction of OC levels may be a risk factor for CAS in T2DM patients.

Acidosis, regardless of hypoxia involvement, is recognized as a chronic and harsh tumor microenvironment (TME) that educates malignant cells to thrive and metastasize. Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression, the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy. Here, chemical-induced and transgenic mouse models for colon, liver and lung cancer were established, respectively. miR-7 and TGF-β2 expressions were examined in clinical tissues (n = 184). RNA-seq, miRNA-seq, proteomics, biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer metastasis. Our data show that lung cancer is sensitive to the increased acidification of TME, and acidic TME-induced lung cancer metastasis via inhibition of miR-7-5p. TGF-β2 is a direct target of miR-7-5p. The reduced expression of miR-7-5p subsequently increases the expression of TGF-β2 which enhances the metastatic potential of the lung cancer. Indeed, overexpression of miR-7-5p reduces the acidic pH-enhanced lung cancer metastasis. Furthermore, the human lung tumor samples also show a reduced miR-7-5p expression but an elevated level of activated TGF-β2; the expressions of both miR-7-5p and TGF-β2 are correlated with patients' survival. We are the first to identify the role of the miR-7/TGF-β2 axis in acidic pH-enhanced lung cancer metastasis. Our study not only delineates how acidification directly affects tumorigenesis, but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer (NSCLC) treatment. Our study opens an avenue to explore the pH-sensitive subcellular components as novel therapeutic targets for cancer treatment.