ABSTRACT
Most proteins are derived from the translation of coding sequence (CDS) in messenger RNAs (mRNAs). However, accumulating evidence has revealed an unexpected abundance of translation in putative non-coding genomes, especially 5' untranslated region (5' UTR) of mRNAs or non-coding RNA species (ncRNA) such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). Notably, many of these UTR- or ncRNA-encoded micropeptides/proteins play important roles in human malignancies. In this review, we describe recent advances in our understanding of the mechanisms underlying the translation of non-coding regions or ncRNAs and the methods to discover the hidden coding information. Furthermore, we summarize the biological functions of UTR- or ncRNA-encoded micropeptides/proteins in cancers and discuss their potential as clinical biomarkers for cancer diagnosis and as therapeutic targets for cancer treatment.
Subject(s)
Neoplasms , RNA, Long Noncoding , Humans , RNA, Untranslated/genetics , RNA, Long Noncoding/genetics , Neoplasms/genetics , Neoplasms/metabolism , RNA, Messenger/genetics , Proteins , MicropeptidesABSTRACT
Inhibitor of growth family member 3 (ING3), a tumor suppressor, plays crucial roles in cell cycle regulation, apoptosis and transcription. Previous studies suggest important roles of nuclear ING3, however, the nuclear localization sequence (NLS) of ING3 is not defined and its biological functions remain to be elucidated. In this study, various ING3 mutants were generated to identify its NLS. The NLS of ING3 was determined as KKFK between 164 and 167 amino acids. More intriguingly, replacement of Lysine 164 residue of ING3 with alanine (K164A) resulted in retention of ING3 in the cytoplasm. Overexpression of ING3 led to inhibition of melanoma cell migration, invasion, and angiogenesis respectively, however, this inhibition was abrogated in cells with overexpression of ING3-K164A mutant. In conclusion, this study identified the NLS of ING3 and demonstrated the significance of ING3 nuclear localization for tumor suppressive functions of ING3, and future studies await to elucidate the role of ING3 (K164) post-modificaton in its nuclear transportation and cancer development.
Subject(s)
Homeodomain Proteins/metabolism , Melanoma/pathology , Neoplasm Invasiveness/pathology , Neovascularization, Pathologic/pathology , Tumor Suppressor Proteins/metabolism , Cell Line, Tumor , Cell Movement , Cell Nucleus/genetics , Cell Nucleus/metabolism , Cell Nucleus/pathology , HEK293 Cells , Homeodomain Proteins/analysis , Homeodomain Proteins/genetics , Humans , Melanoma/genetics , Melanoma/metabolism , Mutation , Neoplasm Invasiveness/genetics , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism , Nuclear Localization Signals/analysis , Nuclear Localization Signals/genetics , Nuclear Localization Signals/metabolism , Tumor Suppressor Proteins/analysis , Tumor Suppressor Proteins/genetics , Up-RegulationABSTRACT
Colorectal cancer (CRC) is one of the most common malignant tumors and is associated with a high mortality rate due to the lack of specific biomarkers available for early diagnosis, targeted therapies, and prognostic surveillance. In the present study, we investigated the function of Numb and its underlying mechanism in CRC. Immunohistochemical staining and clinicopathological analysis were used to assess the expression of Numb and its clinical significance in patients with CRC. Quantitative real-time polymerase chain reaction, cell proliferation, Western blot, wound healing, Transwell, and TOP/FOP flash reporter assays were used to investigate the function of Numb and its underlying mechanism in CRC. Numb expression was downregulated and negatively correlated with the depth of invasion, tumor size, metastasis, TNM stage, and epithelial-to-mesenchymal transition (EMT) markers in CRC specimens. Numb negatively regulates the EMT, proliferation, invasion, migration, and the Wnt signaling pathway in vitro, as well as tumor growth and metastasis in vivo. Furthermore, activation of the Wnt signaling pathway by Wnt-3A negated the effect of Numb overexpression, whereas inhibition of the Wnt signaling pathway by IWR-1 impaired the effect of the Numb knockdown on the EMT. We concluded that Numb downregulation is a common event in patients with CRC and is closely correlated with cancer progression and a poor prognosis. Numb functions as a tumor suppressor in CRC, and its tumor suppressor function is mediated by negative regulation of the EMT through the Wnt signaling pathway.NEW & NOTEWORTHY We investigate the function of Numb and its underlying mechanism in colorectal cancer through quantitative real-time polymerase chain reaction, cell proliferation, Western blot, wound healing, Transwell, and TOP/FOP flash reporter assays. We conclude that Numb can negatively regulate the epithelial-to-mesenchymal transition through the Wnt signaling pathway to inhibit the development of colorectal cancer.
Subject(s)
Colorectal Neoplasms/metabolism , Epithelial-Mesenchymal Transition , Membrane Proteins/metabolism , Nerve Tissue Proteins/metabolism , Wnt Signaling Pathway , Wnt3A Protein/metabolism , Animals , Cell Line, Tumor , Cell Movement , Cell Proliferation , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Membrane Proteins/genetics , Mice, Inbred NOD , Mice, SCID , Middle Aged , Neoplasm Metastasis , Nerve Tissue Proteins/genetics , Tumor Burden , Wnt3A Protein/geneticsABSTRACT
BACKGROUND: We carried out a systematic review and meta-analysis to evaluate the impact of prophylactic dexamethasone on post-operative nausea and vomiting (PONV), post-operative pain, and complications in patients undergoing thyroidectomy. METHODS: We searched Pubmed, Embase, and Cochrane Library databases for randomized controlled trials (RCTs) that evaluated the prophylactic effect of dexamethasone versus placebo with or without other antiemetics for PONV in patients undergoing thyroidectomy. Meta-analyses were performed using RevMan 5.0 software. RESULTS: Thirteen RCTs that considered high quality evidence including 2,180 patients were analyzed. The meta-analysis demonstrated a significant decrease in the incidence of PONV (RR 0.52, 95% CI 0.43 to 0.63, P < 0.00001), the need for rescue anti-emetics (RR 0.42, 95% CI 0.30 to 0.57, P<0.00001), post-operative pain scores (WMD -1.17, 95% CI -1.91 to -0.44, P = 0.002), and the need for rescue analgesics (RR 0.65, 95% CI 0.50-0.83, P = 0.0008) in patients receiving dexamethasone compared to placebo, with or without concomitant antiemetics. Dexamethasone 8-10mg had a significantly greater effect for reducing the incidence of PONV than dexamethasone 1.25-5mg. Dexamethasone was as effective as other anti-emetics for reducing PONV (RR 1.25, 95% CI 0.86-1.81, P = 0.24). A significantly higher level of blood glucose during the immediate post-operative period in patients receiving dexamethasone compared to controls was the only adverse event. CONCLUSIONS: Prophylactic dexamethasone 8-10mg administered intravenously before induction of anesthesia should be recommended as a safe and effective strategy for reducing the incidence of PONV, the need for rescue anti-emetics, post-operative pain, and the need for rescue analgesia in thyroidectomy patients, except those that are pregnant, have diabetes mellitus, hyperglycemia, or contraindications for dexamethasone. More high quality trials are warranted to define the benefits and risks of prophylactic dexamethasone in potential patients with a high risk for PONV.
