Long noncoding RNAs (lncRNAs) are emerging as critical regulatory elements and play fundamental roles in the biology of various cancers. However, we are still lack of knowledge about their expression ...patterns and functions in human colorectal cancer (CRC).
Differentially expressed lncRNAs in CRC were identified by bioinformatics screen and the level of MIR22HG in CRC and control tissues were determined by qRT-PCR. Cell viability and migration capacities were examined by MTT and transwell assay. Mouse model was used to examine the function and rational immunotherapy of MIR22HG in vivo.
We systematically investigated the expression pattern of lncRNAs and revealed MIR22HG acts as a tumor suppressor in CRC. The expression of MIR22HG was significantly decreased in CRC, which was mainly driven by copy number deletion. Reduced expression of MIR22HG was significantly associated with poor overall survival. Silencing of MIR22HG promoted cell survival, proliferation and tumor metastasis in vitro and in vivo. Mechanistically, MIR22HG exerts its tumor suppressive activity by competitively interacting with SMAD2 and modulating the activity of TGFβ pathway. Decreased MIR22HG promoted the epithelial-mesenchymal transition in CRC. Importantly, we found that MIR22HG expression is significantly correlated with CD8A and overexpression of MIR22HG triggers T cell infiltration, enhancing the clinical benefits of immunotherapy.
MIR22HG acts as a tumor suppressor in CRC. Our data provide mechanistic insights into the regulation of MIR22HG in TGFβ pathway and facilitates immunotherapy in cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
miR-204-5p was found to be downregulated in colorectal cancer tissues in our preliminary microarray analyses. However, the function of miR-204-5p in colorectal cancer remains unknown. We therefore ...investigated the role, mechanism, and clinical significance of miR-204-5p in colorectal cancer development and progression.
We measured the expression of miR-204-5p and determined its correlation with patient prognoses. Ectopic expression in colorectal cancer cells, xenografts, and pulmonary metastasis models was used to evaluate the effects of miR-204-5p on proliferation, migration, and chemotherapy sensitivity. Luciferase assay and Western blotting were performed to validate the potential targets of miR-204-5p after the preliminary screening by a microarray analysis and computer-aided algorithms.
miR-204-5p is frequently downregulated in colorectal cancer tissues, and survival analysis showed that the downregulation of miR-204-5p in colorectal cancer was associated with poor prognoses. Ectopic miR-204-5p expression repressed colorectal cancer cell growth both in vitro and in vivo. Moreover, restoring miR-204-5p expression inhibited colorectal cancer migration and invasion and promoted tumor sensitivity to chemotherapy. Mechanistic investigations revealed that RAB22A, a member of the RAS oncogene family, is a direct functional target of miR-204-5p in colorectal cancer. Furthermore, RAB22A protein levels in colorectal cancer tissues were frequently increased and negatively associated with miR-204-5p levels and survival time.
Our results demonstrate for the first time that miR-204-5p acts as a tumor suppressor in colorectal cancer through inhibiting RAB22A and reveal RAB22A to be a new oncogene and prognostic factor for colorectal cancer.
Colorectal cancer (CRC) is a common cancer worldwide, with a lower 5-years survival rate. Recently, long non-coding RNAs (lncRNAs) have been well-studied as the oncogenes or the tumor suppressors in ...multiple malignancies, including CRC. However, their biological functions and potential mechanisms in human cancer remain unclear. Here, we evaluated the expression of
TDRKH-AS1
in CRC tissues and identified its potential targets. We found that
TDRKH-AS1
is upregulated in majority of CRC patients, which is also significantly correlated with their malignant characteristics and their dismal prognoses. The high expression of
TDRKH-AS1
can promote cancer cell proliferation substantially and invasion based on
in vitro
experiments. We also recognized that the
TDRKH-AS1
targets the β-catenin in the
Wnt
signaling pathway to exert its carcinogenic activity.
TDRKH-AS1
could serve as a promising prognostic predictor and a potential therapeutic target for further early diagnoses and treatments via a non-invasive method.
A stairs-type global strain clocking mechanism for nanomagnetic majority logic gate based on shape engineering of nanomagnets was designed in this paper. Reasonable size nanomagnets and proper strain ...clocking scheme ensure the computing architecture pipelined at room temperature. The optimal global strain clocking scheme was obtained by investigating the impact of magnetic layer thickness and width on clocking period and strain magnitude. Encouragingly, for the global strain clocking, information transmission speed of majority logic gate is increased 1-2 times as against the local strain clocking scheme due to decreasing the number of start-ups during information transmission. While the energy dissipated per clock cycle of the global strain clocking scheme consumes 3-4 times less energy than that of local strain clocking scheme. Moreover, global clocking is used to control a nanomagnetic logic device(NMLD), in which case single device consisted of many nanomagnets can be treated as single nanomagnet. However, magnetization switching is error-prone in the presence of thermal noise at room temperature. Therefore, the proper structure parameters of the device are obtained at room temperature, in which case the error probability of the majority logic gate is 0.5% in theoretical simulation. These results provide essential guidance for the design of energy-efficient multiferroic nanomagnetic logic devices.
This study systematically analyzed the molecular mechanism and function of nuclear factor kappa B subunit 2 (NFKB2) in colorectal cancer (CRC) to investigate the potential of NFKB2 as a therapeutic ...target for CRC. Various experimental techniques, including RNA sequencing, proteome chip assays, and small molecule analysis, were used to obtain a deeper understanding of the regulation of NFKB2 in CRC. The results revealed that NFKB2 was upregulated in a significant proportion of patients with advanced hepatic metastasis of CRC. NFKB2 played an important role in promoting tumor growth through CD8+ T‐cell exhaustion. Moreover, NFKB2 directly interacted with signal transducer and activator of transcription 2 (STAT2), leading to increased phosphorylation of STAT2 and the upregulation of programmed death ligand 1 (PD‐L1). Applying a small molecule inhibitor of NFKB2 (Rg5) led to a reduction in PD‐L1 expression and improved response to programmed death‐1 blockade‐based immunotherapy. In conclusion, the facilitated NFKB2‐STAT2/PD‐L1 axis may suppress immune surveillance in CRC and targeting NFKB2 may enhance the efficacy of immunotherapeutic strategies. Our results provide novel insights into the molecular mechanisms underlying the contribution of NFKB2 in CRC immune escape.
Amplification of 10q24.32 in CRC resulted in upregulation of NFKB2 protein levels, which directly interacts with STAT2, leading to STAT2 protein stabilization and phosphorylation, and consequently, further upregulating PD‐L1. Rg5, a small‐molecule inhibitor of NFKB2, could break the NFKB2‐STAT2 interaction, with significant reduced PD‐L1 expression and alleviated CD8+ T‐cell exhaustion, leading to an enhanced sensitivity to PD‐1 blockade‐based immunotherapy.
MicroRNAs （miRNAs） are a type of small non-coding RNAs that are often play important roles in carcinogene- sis, but the carcinogenic mechanism of miRNAs is still unclear. This study will investigate ...the function and the mechanism of miR-638 in carcinoma （GC）. The expres- sion of miR-638 in GC and the DNA copy number of miR- 638 were detected by real-time PCR. The effect of miR-638 on cell proliferation was measured by counting kit-8 assay. Different assays, including bioinformatics algo- rithms （TargetScan and miRanda）, luciferase report assay and Western blotting, were used to identify the target gene of miR-638 in GC. The expression of miR-638 target gene in clinical CRC tissues was also validated by immunohistochemical assay. From this research, we found that miR-638 was downregulated in GC tissues compared with corresponding noncancerous tissues （NCTs）, and the DNA copy number of miR-638 was lower in GC than NCTs, which may induce the corresponding downregulation of miR-638 in GC. Ectopic expression of miR-638 inhibited GC cell growth in vitro. Subsequently, we identified that PLD1 is the target gene of miR-638 in GC, and silencing PLD1 expression phenocopied the inhibitory effect of miR-638 on GC cell proliferation. Fur- thermore, we observed that PLD1 was overexpressed inGC tissues, and high expression of PLDt in GC predicted poor overall survival. In summary, we revealed that miR- 638 functions as a tumor suppressor in GC through inhibiting PLDI.
RNA-binding proteins (RBPs) play fundamental roles in cancer; however, we still lack knowledge about to what extent RBPs are dysregulated, as well as about perturbed signaling pathways in cancer. In ...this study, we integrated analysis of multidimensional data across >10,000 cancer patients and >1,000 cell lines. We identified a top candidate RBP: eukaryotic translation initiation factor 2 subunit beta (EIF2S2). EIF2S2 is highly expressed in tumors and is associated with malignant features as well as patient prognosis. Functional assays performed in cancer cells revealed that EIF2S2 promotes cancer cell proliferation, migration, and invasion in vitro as well as tumor growth and metastasis in vivo. Mechanistic investigations further demonstrated that EIF2S2 promotes tumorigenesis and progression by directly binding to a long non-coding RNA, LINC01600, which physically interacts with the MYC protein and increases its stability. Interestingly, we revealed that the EIF2S2-LINC01600-MYC axis can activate the Wnt/β-catenin pathway by inhibiting the activity of FHIT-related enhancers and FHIT expression. Finally, EIF2S2 knockdown combined with oxaliplatin treatment could be a potential combination therapy in cancer. Our integrated analysis provided detailed knowledge of the function of the EIF2S2-LINC01600-MYC axis, which will facilitate the development of rational combination therapies for cancer.
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RNA-binding proteins play important roles in cancer. Li et al. integrated multiple omics data that identified a potential oncogene, EIF2S2. Functional analyses provided detail knowledge of the function of the EIF2S2-LINC01600-MYC axis in gastrointestinal cancer, which will help the development of combination therapies for cancer.
In this study, an improved static Duhem model (SDM) based on the interior point algorithm is proposed to characterize the asymmetric hysteresis of the piezo-actuated micropositioning stage (PAMS). To ...further describe the dynamic hysteresis, the diagonal recurrent neural network and SDM are cascaded to establish an online dynamic Duhem model. For the controller implementation, a static inverse compensation controller utilizing an inverse multiplicative structure is devised to compensate for the static hysteresis of the PAMS. Moreover, a dynamic inverse compensation controller (DICC) with online parameter adjustment is proposed to address challenges related to trajectory tracking control. The convergence of the DICC is proved through the Lyapunov stability theorem. A series of comparative experiments are conducted on the PAMS to validate the effectiveness of the proposed model and control algorithm.
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•An improved Duhem model is presented to describe the hysteresis of PAMS.•A neural network-based controller is proposed to eliminate hysteresis.•The comparative experiments demonstrate the effectiveness of the proposed methods.
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