ABSTRACT
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.
ABSTRACT
Objective To explore methods to develop a hospital quality of care index system of county level hospitals based on the homepage of inpatient medical records and examine the validity of this system. Methods By means of literature review, homepage data and panel discussion, along with theories and statistical methods, indexes were identified. The dimensions and indices of the index system were pinpointed. Confirmatory factor analysis and normalization methods were combined to calculate the weights and scores of such indices. Scores were adjusted by Charlson comorbidity index ( CCI) with multi-regression method. The hospitals were ranked by adjusted scores in each dimension. The validity was evaluated by comparing the application results to universally acknowledged standards, such as hospital level and economic level of the geographic areas. Results An index system with 6 dimensions and 25 indices was developed, and the application results proved valid to some extent. The adjustment of CCI also proved effective. The 6 dimensions were correlated yet their directions were not consistent. Conclusions The methods and data used to develop the system have demonstrated strong operability and availability. The application results can reflect medical care quality in different aspects making it applicable among homogeneous hospitals. It is meaningful to assess dimensions respectively.