Mitochondrial ribosome proteins (MRPs), which are encoded by the nuclear genomic DNA, are important for mitochondrial-encoded protein synthesis and mitochondrial function. Emerging evidence suggests that several MRPs also exhibit important extra-mitochondrial functions, such as involvement in apoptosis, protein biosynthesis, and signal transduction. In this study, we demonstrate a significant role of MRP L35 (MRPL35) in colorectal cancer (CRC). The expression of MRPL35 was higher in CRC tissues than in matched cancer-adjacent tissues and higher in CRC cells than in normal mucosal epithelial cells. Higher MRPL35 expression in CRC tissue correlated with shorter overall survival for CRC patients. In vitro, down-regulation of MRPL35 led to increased production of reactive oxygen species (ROS) together with DNA damage, loss of cell proliferation, G 2 /M arrest, a decrease in mitochondrial membrane potential, apoptosis, and autophagy induction. MRPL35 knockdown inhibited tumor proliferation in a CRC xenograft nude mouse model. Furthermore, overexpression of MRPL35 or treatment of cells with the ROS scavenger, N-acetyl cysteine, abrogated ROS production, cell cycle arrest, and apoptosis in vitro. These findings suggest that MRPL35 plays an essential role in the development of CRC and may be a potential therapeutic target for CRC. (Am J Pathol 2019, 189: 1105e1120; https:// Colorectal cancer (CRC), characterized by fast progression and poor prognosis, is one of the most common malignancies in the world. 1 The mechanisms of CRC development are still poorly understood. Although surgery is the most effective therapy for CRC, chemotherapy and radiotherapy are still indispensable. 2 Side effects and drug resistance are common issues with most of these treatments reducing their efficacy. As a consequence, CRC is in urgent need of markers for early diagnosis and of intervention targets for effective therapy.Mitochondria have a central role in cellular energy metabolism by oxidative phosphorylation, regulation of apoptosis, autophagy, and cell death. 3e5 Defective mitochondrial functions have been thought to be possible underlying mechanisms for cancer. 6,7 Mitochondria have their own DNA and ribosomes (mitoribosomes), which produce 13 proteins essential for oxidative phosphorylation. 8 Human mitoribosomes sediment as 55S particles, consisted of a 28S small subunit, formed by a 12S rRNA and 29 mitochondrial ribosome proteins (MRPs), and a 39S large subunit, formed by a 16S rRNA and 50 MRPs. 9,10 The approximately 70 MRPs are encoded by nuclear genomic DNA, synthesized in the cytosol,
Ras-specific guanine nucleotide-releasing factor 2 (RasGRF2) is a member of the guanine nucleotide exchange factors family which is expressed in a variety of tissues and cancer. However, the role of RasGRF2 in cancer is less reported, especially in colorectal cancer(CRC). Hence, the present study aimed to investigated the function of RasGRF2 and ways in which it affects tumor progression in CRC samples and cell lines. We first measured RasGRF2 mRNA level in 26 paired tumor and nontumor colon tissues after colon cancer surgical resection, and determined RasGRF2 protein level in 97 paired paraffinembedded colon cancer tissues, and found that levels of RasGRF2 mRNA and protein were increased in colorectal tumor tissues, compared with adjacent non-tumor tissues. We then examined the effects of RasGRF2 knockdown on proliferation, migration and invasion were analyzed in CRC cells (SW480, HCT116 and LS174T). HCT116 cells with RasGRF2 knockdown were injected into the tail vein in nude mice to yield metastatic model, and tumor metastasis was measured as well. We found that knockdown of RasGRF2 in CRC cells reduced their migration and invasion in vitro and metastasis in mice. Furthermore, we explored the underlying molecular mechanism for RasGRF2-mediated CRC migration and invasion. The results showed that knockdown of RasGRF2 in CRC cells impairing the expression of MMP9 and inhibiting the activation of Src/Akt and NF-κB signaling. We conclude that RasGRF2 plays a role in controlling migration and invasion of CRC and modulates the expression of MMP9 through Src/PI 3-kinase and the NF-κB pathways. ARTICLE HISTORY
A novel small peptide, ωRWR, has been developed with a good stability for possible antithrombotic use.
Objective: To study the influence on coagulant of patients with cancer by PICC placement. Methods: To test the plasma levels of D-dimer(D-D),prothrombin(PT),activated partial thromplasmtin(APTT),thrombin time(TT),antithrombin(ATⅢ),fibrinogen(Fib) and platelet count by ELISA in 46 patients with cancer in one day before PICC placement, in one day,30 day, and 90 day after PICC placement, and analyses the change feature and clinical significance. Results: (1)The levels of plasma D-D were higher than control group in both pre-PICC placement and post-PICC placement, but there were no differences in both pre-PICC placement and post-PICC placement(P>0.05).(2)The levels of plasma PT, APTT,TT,ATⅢ,Fib and platelet were not different in both pre-PICC placement and post-PICC placement(all P>0.05),and there were no differences from control group.(3)There were no cases with thromboembolism in 48 cancer patients without PICC placement, and 3 cases of thromboembolism occurred among 88 cancer patients treated with PICC placement. But there were no significances(P=0.27). Conclusion: Therelevels of D-D,PT,APTT,TT,ATⅢ, Fib and platelet in patients with cancer did not change in both pre-PICC placement and post-PICC placement. There was no effect of coagulant on patients with cancer by PICC placement. The PICC placement was safe.
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