The epidermal growth factor receptor (EGFR)/RAS/RAF/MEK/MAPK pathway plays a crucial role in the carcinogenesis, invasion and metastasis of colorectal cancer (CRC). However, its role in the prognosis and prediction of relapse in patients with stage III CRC after adjuvant chemotherapy remains controversial. In the present study, the clinicopathological features of 173 patients with stage III CRC who underwent radical resection and adjuvant chemotherapy with the fluoropyrimidine/folinic acid, and oxaliplatin (FOLFOX) regimen, and their prognostic values of EGFR expression were retrospectively analyzed. By conducting an in vitro CRC cell line study through the knockdown of EGFR expression, we analyzed cell proliferation, colony formation and migration. Positive EGFR expression and an abnormal postoperative serum carcinoembryonic antigen (CEA) level were found to be significant independent negative predictive factors for postoperative relapse. Furthermore, positive EGFR expression was a significant independent negative prognostic factor for disease-free survival (DFS) and overall survival (OS). Additionally, an in vitro cell line study showed that the knockdown of EGFR expression significantly reduced CRC cell proliferation, colony formation and migration. The results of in vitro and in vivo experiments demonstrated that EGFR expression had a prognostic value for OS and DFS, as well as predictive roles for postoperative relapse, in patients with stage III CRC. By analyzing both EGFR expression and the postoperative CEA, the patients with stage III CRC who were at a high risk of postoperative relapse, or mortality following adjuvant chemotherapy could be identified. In short, CRC cells with EGFR expression would exhibit a highly malignant behavior.
Lack of mechanical stress may result in osteoporosis; however, the underlying mechanisms of disuse osteoporosis remain unclear. It has been indicated that mechanical loading causes extracellular glutamate accumulation in osteoblasts. We hypothesized that the glutamate receptor mediation on bone cells might also be involved in mechanically stimulated osteogenesis. In this study, we investigated the changes of bone formation and the expressions of osteogenic genes and N-methyl D-aspartate (NMDA) receptors, the major glutamate receptors, in disused bones. Rat modeled disuse osteopenia in hind limbs was induced by a 3-week tail suspension in Sprague-Dawley rats. Bone mineral density and trabecular bone volume of distal femurs were measured to verify the osteopenia of disused bones. The mRNA expressions of cbfa1/Runx2, type I collagen, alkaline phosphatase (ALP) and osteocalcin (OC) in bones were measured as osteogenic markers. The influences of mechanical unloading on the expressions of NMDA receptors (NR1 and NR2D) in bones were also examined. The effects of NMDA mediation on osteogenesis were tested by a treatment of MK-801, a non-competitive NMDA receptor antagonist, in cultured osteoblasts and bone marrow stroma cells. Our result showed that mRNA expressions of cbfa1/Runx2, type I collagen, ALP and OC were significantly decreased in disused bones. The mRNA and protein expressions of NR1 and NR2D were significantly decreased in disused bones; furthermore, immunolocalization of both receptors showed decreases in osteoblasts, but not in osteoclasts. The results from the in vitro study showed that MK-801 inhibited mRNA expression of cbfa1/Runx2 in bone marrow stroma cells and also inhibited those of collagen type I, ALP and OC of osteoblasts in a dose-dependent manner. These results suggest that NMDA receptor mediation may play an important role in transmitting mechanical loading in bones, and decreases of the expressions of NMDA receptors in disused bones, especially in osteoblasts, may contribute to the decrease of osteogenesis.
Colorectal cancer (CRC) is the third most common cancer worldwide. The incidence and mortality rates of CRC are significantly higher in Taiwan than in other developed countries. Genes involved in CRC tumorigenesis differ depending on whether the tumor occurs on the left or right side of the colon, and genomic analysis is a keystone in the study and treatment of CRC subtypes. However, few studies have focused on the genetic landscape of Taiwanese patients with CRC. This study comprehensively analyzed the genomes of 141 Taiwanese patients with CRC through whole-exome sequencing. Significant genomic differences related to the site of CRC development were observed. Blood metabolomic profiling and polygenic risk score analysis were performed to identify potential biomarkers for the early identification and prevention of CRC in the Taiwanese population. Our findings provide vital clues for establishing population-specific treatments and health policies for CRC prevention in Taiwan.
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