miR-19b-3p promotes colon cancer proliferation and oxaliplatin-based chemoresistance by targeting SMAD4: validation by bioinformatics and experimental analyses

Abstract Background As a disease with extremely complex molecular mechanisms, many deregulated miRNAs have been identified in colon cancer. Few studies have been performed by using Ingenuity Pathways Analysis (IPA) to predict miRNAs specifically expressed in colon cancer. Methods A characteristic microRNA-target network of colon cancer was explored using IPA. Then the clinical significance of miR-19b-3p was evaluated in 211 colon cancer patients. The roles of miR-19b-3p and its candidate target gene, SMAD4, in colon cancer progression were examined both in vitro and in vivo. Results Bioinformatics analysis showed that 15 microRNAs screened by IPA were significantly correlated with malignant biological behaviors of colon cancer. miR-19b-3p was the most significantly upregulated candidate based on the validation experiment using 211 colon cancer samples. High expression of miR-19b-3p was significantly associated with high N stage (P < 0.001), high AJCC stage (P < 0.001), poor histologic grade (P = 0.032), frequent venous and lymphatic invasion (P = 0.027), and liver metastasis (P < 0.001). Survival analysis revealed that miR-19b-3p was an independent prognostic factor associated with colon cancer patient’s overall survival (OS) and disease-free survival (DFS). miR-19b-3p promoted proliferation and chemoresistance of colon cancer cells, but had no effect on invasion in vitro, along with tumorigenesis in vivo. In addition, we confirmed that miR-19b-3p mediates resistance to oxaliplatin-based chemotherapy via SMAD4. Conclusions Our findings demonstrate the role of miR-19b-3p-SMAD4 axis in colon cancer progression, which may become a potential therapeutic target against chemotherapy resistance

Overexpression of GRK3, Promoting Tumor Proliferation, Is Predictive of Poor Prognosis in Colon Cancer

Deregulation of G protein-coupled receptor kinase 3 (GRK3), which belongs to a subfamily of kinases called GRKs, acts as a promoter mechanism in some cancer types. Our study found that GRK3 was significantly overexpressed in 162 pairs of colon cancer tissues than in the matched noncancerous mucosa (P<0.01). Based on immunohistochemistry staining of TMAs, GRK3 was dramatically stained positive in primary colon cancer (130/180, 72.22%), whereas it was detected minimally or negative in paired normal mucosa specimens (50/180, 27.78%). Overexpression of GRK3 was closely correlated with AJCC stage (P=0.001), depth of tumor invasion (P<0.001), lymph node involvement (P=0.004), distant metastasis (P=0.016), and histologic differentiation (P=0.004). Overexpression of GRK3 is an independent prognostic indicator that correlates with poor survival in colon cancer patients. Consistent with this, downregulation of GRK3 exhibited decreased cell growth index, reduction in colony formation ability, elevated cell apoptosis rate, and impaired colon tumorigenicity in a xenograft model. Hence, a specific overexpression of GRK3 was observed in colon cancer, GRK3 potentially contributing to progression by mediating cancer cell proliferation and functions as a poor prognostic indicator in colon cancer and potentially represent a novel therapeutic target for the disease

Functional and mechanistic investigation of Shikonin in scarring

Scarring is a significant medical burden; financially to the health care system and physically and psychologically for patients. Importantly, there have been numerous case reports describing the occurrence of cancer in burn scars. Currently available therapies are not satisfactory due to their undesirable side-effects, complex delivery routes, requirements for long-term use and/or expense. Radix Arnebiae (Zi Cao), a perennial herb, has been clinically applied to treat burns and manage scars for thousands of years in Asia. Shikonin, an active component extracted from Radix Arnebiae, has been demonstrated to induce apoptosis in cancer cells. Apoptosis is an essential process during scar tissue remodelling. It was therefore hypothesized that Shikonin may induce apoptosis in scar-associated cells. This investigation presents the first detailed in vitro study examining the functional responses of scar-associated cells to Shikonin, and investigates the mechanisms underlying these responses. The data obtained suggests that Shikonin inhibits cell viability and proliferation and reduces detectable collagen in scar-derived fibroblasts. Further investigation revealed that Shikonin induces apoptosis in scar fibroblasts by differentially regulating the expression of caspase 3, Bcl-2, phospho-Erk1/2 and phospho-p38. In addition, Shikonin down-regulates the expression of collagen I, collagen III and alpha-smooth muscle actin genes hence attenuating collagen synthesis in scar-derived fibroblasts. In summary, it is demonstrated that Shikonin induces apoptosis and decreases collagen production in scar-associated fibroblasts and may therefore hold potential as a novel scar remediation therapy

Compensation of the magnetic force imaging by scanning directions

It was found that the results of magnetic force microscope (MFM) imaging were different with the probe scanning directions. This paper studied the effect of scanning directions on the MFM imaging, and a method for the distortion compensation was proposed to reduce the errors. In the study, three different scanning directions with the angles of 0°, 45° and 90° were used to measure the magnetic domain structures distributions of magnetic sample. The experimental results have shown that the scanning direction parallel to the magnetic domain structure will cause a minimum phase shift difference and lead to a structure distortion. A method for compensating the distortions was proposed. With this method, the distorted structures were corrected and the effect of scanning directions on the MFM imaging was significantly reduced. This work provides a way for the acquisition of the correct images of magnetic structures using an MFM and the improvement of imaging quality in a wide range of MFM applications

Additional file 2: Table S2. of miR-19b-3p promotes colon cancer proliferation and oxaliplatin-based chemoresistance by targeting SMAD4: validation by bioinformatics and experimental analyses

miRNAs specifically expressed in colon cancer after being screened by IPA. (DOCX 26 kb

Additional file 1: Table S1. of miR-19b-3p promotes colon cancer proliferation and oxaliplatin-based chemoresistance by targeting SMAD4: validation by bioinformatics and experimental analyses

Oligonucleotide Sequence for the primers used in the study. (DOCX 25 kb

Additional file 3: Table S3. of miR-19b-3p promotes colon cancer proliferation and oxaliplatin-based chemoresistance by targeting SMAD4: validation by bioinformatics and experimental analyses

The association between miR-19b-3p and SMAD4 expression. (DOCX 19 kb