Collagen XVII promotes dormancy of colorectal cancer cells by activating mTORC2 signaling.

Tumor dormancy is the underpinning for cancer relapse and chemoresistance, leading to massive cancer-related death in colorectal cancer (CRC). However, our comprehension of the mechanisms dictating tumor dormancy and strategies for eliminating dormant tumor cells remains restricted. In this study, we identified that collagen XVII (COL17A1), a hemidesmosomal transmembrane protein, can promote the dormancy of CRC cells. The upregulation of COL17A1 was observed to prolong quiescence periods and diminish drug susceptibility of CRC cells. Mechanistically, COL17A1 acts as a scaffold, enhancing the crosstalk between mTORC2 and Akt, thereby instigating the mTORC2-mediated dormant signaling. Notably, the activation of mTORC2 is contingent upon the intracellular domain of COL17A1, regardless of its ectodomain shedding. Our findings underscore a pivotal role of the COL17A1-mTORC2 axis in CRC dormancy, suggesting that mTORC2-specific inhibitors may hold therapeutic prospects for the eradication of dormant tumor cells.

Mex-3 RNA binding family member A (MEX3A)/circMPP6 complex promotes colorectal cancer progression by inhibiting autophagy.

RNA-binding proteins (RBPs)-RNA networks have contributed to cancer development. Circular RNAs (circRNAs) are considered as protein recruiters; nevertheless, the patterns of circRNA-protein interactions in colorectal cancer (CRC) are still lacking. Processing bodies (PBs) formed through liquid-liquid phase separation (LLPS) are membrane-less organelles (MLOs) consisting of RBPs and RNA. Previous evidence suggests a connection between PBs dynamics and cancer progression. Despite the increasingly acknowledged crucial role of RBPs and RNA in the accumulation and maintenance of MLOs, there remains a lack of specific research on the interactions between PBs-related RBPs and circRNAs in CRC. Herein, we identify that MEX-3 RNA binding family member A (MEX3A), frequently upregulated in CRC tissues, predicts poorer patient survival. Elevated MEX3A accelerates malignance and inhibits autophagy of CRC cells. Importantly, MEX3A undergoes intrinsically disordered regions (IDRs)-dependent LLPS in the cytoplasm. Specifically, circMPP6 acts as a scaffold to facilitate the interaction between MEX3A and PBs proteins. The MEX3A/circMPP6 complex modulates PBs dynamic and promotes UPF-mediated phosphodiesterase 5A (PDE5A) mRNA degradation, consequently leading to the aggressive properties of CRC cells. Clinically, CRC patients exhibiting high MEX3A expression and low PDE5A expression have the poorest overall survival. Our findings reveal a collaboration between MEX3A and circMPP6 in the regulation of mRNA decay through triggering the PBs aggregation, which provides prognostic markers and/or therapeutic targets for CRC.

The analysis on groundwater storage variations from GRACE/GRACE-FO in recent 20 years driven by influencing factors and prediction in Shandong Province, China.

Monitoring and predicting the regional groundwater storage (GWS) fluctuation is an essential support for effectively managing water resources. Therefore, taking Shandong Province as an example, the data from Gravity Recovery and Climate Experiment (GRACE) and GRACE Follow-On (GRACE-FO) is used to invert GWS fluctuation from January 2003 to December 2022 together with Watergap Global Hydrological Model (WGHM), in-situ groundwater volume and level data. The spatio-temporal characteristics are decomposed using Independent Components Analysis (ICA), and the impact factors, such as precipitation and human activities, which are also analyzed. To predict the short-time changes of GWS, the Support Vector Machines (SVM) is adopted together with three commonly used methods Long Short-Term Memory (LSTM), Singular Spectrum Analysis (SSA), Auto-Regressive Moving Average Model (ARMA), as the comparison. The results show that: (1) The loss intensity of western GWS is significantly greater than those in coastal areas. From 2003 to 2006, GWS increased sharply; during 2007 to 2014, there exists a loss rate - 5.80 ± 2.28 mm/a of GWS; the linear trend of GWS change is - 5.39 ± 3.65 mm/a from 2015 to 2022, may be mainly due to the effect of South-to-North Water Diversion Project. The correlation coefficient between GRACE and WGHM is 0.67, which is consistent with in-situ groundwater volume and level. (2) The GWS has higher positive correlation with monthly Global Precipitation Climatology Project (GPCP) considering time delay after moving average, which has the similar energy spectrum depending on Continuous Wavelet Transform (CWT) method. In addition, the influencing facotrs on annual GWS fluctuation are analyzed, the correlation coefficient between GWS and in-situ data including the consumption of groundwater mining, farmland irrigation is 0.80, 0.71, respectively. (3) For the GWS prediction, SVM method is adopted to analyze, three training samples with 180, 204 and 228 months are established with the goodness-of-fit all higher than 0.97. The correlation coefficients are 0.56, 0.75, 0.68; RMSE is 5.26, 4.42, 5.65 mm; NSE is 0.28, 0.43, 0.36, respectively. The performance of SVM model is better than the other methods for the short-term prediction.

An improved sparrow search algorithm and CNN-BiLSTM neural network for predicting sea level height.

Accurate prediction of sea level height is critically important for the government in assessing sea level risk in coastal areas. However, due to the nonlinear, time-varying and highly uncertain characteristics of sea level change data, sea level prediction is challenging. To improve the accuracy of sea level prediction, this paper uses a new swarm intelligence algorithm named the sparrow search algorithm (SSA), which can imitate the foraging behavior and antipredation behavior of sparrows, to determine optimal solutions. To avoid the algorithm falling into a local optimal situation, this paper integrates the sine-cosine algorithm and the Cauchy variation strategy into the SSA to obtain an algorithm named the SCSSA. The SCSSA is used to optimize the parameter values of the CNN-BiLSTM (convolutional neural network combined with bidirectional long short-term memory neural network) model; finally, a combined neural network model (named SCSSA-CNN-BiLSTM) is proposed. In this paper, the time series data of seven tidal stations located in coastal China are used for experimental analysis. First, the SCSSA-CNN-BiLSTM model is compared with the CNN-BiLSTM model to predict the time series data of SHANWEI Station. With respect to the training and test sets of data, the SCSSA-CNN-BiLSTM model outperforms the other models on all the evaluation metrics. In addition, the remaining six tide station datasets and five neural network models, including the SCSSA-CNN-BiLSTM model, are used to further study the performance of the proposed prediction model. Four evaluation indices including the root mean squared error (RMSE), mean absolute error (MAE), mean absolute percentage error (MAPE) and coefficient of determination (R2) are adopted. For six stations, the RMSE, MAE, MAPE and R2 of SCSSA-CNN-BiLSTM model are ranged from 20.9217 ~ 27.8427 mm, 9.4770 ~ 17.8603 mm, 0.1322% ~ 0.2482% and 0.9119 ~ 0.9759, respectively. The experimental analysis results show that the SCSSA-CNN-BiLSTM model makes effective predictions at all stations, and the prediction performance is better than that of the other models. Even though the combination of SCSSA algorithm may increase the complexity of the model, indeed the proposed model is a new prediction method with good accuracy and robustness for predicting sea level change.

NEIL1 drives the initiation of colorectal cancer through transcriptional regulation of COL17A1.

Deficiency of DNA repair pathways drives the development of colorectal cancer. However, the role of the base excision repair (BER) pathway in colorectal cancer initiation remains unclear. This study shows that Nei-like DNA glycosylase 1 (NEIL1) is highly expressed in colorectal cancer (CRC) tissues and associated with poorer clinical outcomes. Knocking out neil1 in mice markedly suppresses tumorigenesis and enhances infiltration of CD8+ T cells in intestinal tumors. Furthermore, NEIL1 directly forms a complex with SATB2/c-Myc to enhance the transcription of COL17A1 and subsequently promotes the production of immunosuppressive cytokines in CRC cells. A NEIL1 peptide suppresses intestinal tumorigenesis in ApcMin/+ mice, and targeting NEIL1 demonstrates a synergistic suppressive effect on tumor growth when combined with a nuclear factor κB (NF-κB) inhibitor. These results suggest that combined targeting of NEIL1 and NF-κB may represent a promising strategy for CRC therapy.

YTHDC1 delays cellular senescence and pulmonary fibrosis by activating ATR in an m6A-independent manner.

Accumulation of DNA damage in the lung induces cellular senescence and promotes age-related diseases such as idiopathic pulmonary fibrosis (IPF). Hence, understanding the mechanistic regulation of DNA damage repair is important for anti-aging therapies and disease control. Here, we identified an m6A-independent role of the RNA-binding protein YTHDC1 in counteracting stress-induced pulmonary senescence and fibrosis. YTHDC1 is primarily expressed in pulmonary alveolar epithelial type 2 (AECII) cells and its AECII expression is significantly decreased in AECIIs during fibrosis. Exogenous overexpression of YTHDC1 alleviates pulmonary senescence and fibrosis independent of its m6A-binding ability, while YTHDC1 deletion enhances disease progression in mice. Mechanistically, YTHDC1 promotes the interaction between TopBP1 and MRE11, thereby activating ATR and facilitating DNA damage repair. These findings reveal a noncanonical function of YTHDC1 in delaying cellular senescence, and suggest that enhancing YTHDC1 expression in the lung could be an effective treatment strategy for pulmonary fibrosis.

Dual specific phosphatase 4 suppresses ferroptosis and enhances sorafenib resistance in hepatocellular carcinoma.

AIMS: This investigation aims to elucidate the mechanism underlying sorafenib-induced ferroptosis in hepatocellular carcinoma (HCC). METHODS: The role of dual specificity phosphatase 4 (DUSP4) in sorafenib-treated HCC was investigated using comprehensive assessments both in vitro and in vivo, including Western blotting, qRT-PCR, cell viability assay, lipid reactive oxygen species (ROS) assay, immunohistochemistry, and xenograft tumor mouse model. Additionally, label-free quantitative proteomics was employed to identify potential proteins associated with DUSP4. RESULTS: Our study revealed that suppression of DUSP4 expression heightens the susceptibility of HCC cells to ferroptosis inducers, specifically sorafenib and erastin, in both in vitro and in vivo settings. Furthermore, we identified DUSP4-mediated regulation of key ferroptosis-related markers, such as ferritin light chain (FTL) and ferritin heavy chain 1 (FTH1). Notably, label-free quantitative proteomics unveiled the phosphorylation of threonine residue T148 on YTH Domain Containing 1 (YTHDC1) by DUSP4. Further investigations unraveled that YTHDC1, functioning as an mRNA nuclear export regulator, is a direct target of DUSP4, orchestrating the subcellular localization of FTL and FTH1 mRNAs. Significantly, our study highlights a strong correlation between elevated DUSP4 expression and sorafenib resistance in HCC. CONCLUSIONS: Our findings introduce DUSP4 as a negative regulator of sorafenib-induced ferroptosis. This discovery opens new avenues for the development of ferroptosis-based therapeutic strategies tailored for HCC treatment.

KRAS status predicted by pretreatment MRI radiomics was associated with lung metastasis in locally advanced rectal cancer patients.

BACKGROUND: Mutated KRAS may indicate an invasive nature and predict prognosis in locally advanced rectal cancer (LARC). We aimed to establish a radiomic model using pretreatment T2W MRIs to predict KRAS status and explore the association between the KRAS status or model predictions and lung metastasis. METHODS: In this retrospective multicentre study, LARC patients from two institutions between January 2012 and January 2019 were randomly divided into training and testing cohorts. Least absolute shrinkage and selection operator (LASSO) regression and the support vector machine (SVM) classifier were utilized to select significant radiomic features and establish a prediction model, which was validated by radiomic score distribution and decision curve analysis. The association between the model stratification and lung metastasis was investigated by Cox regression and Kaplan‒Meier survival analysis; the results were compared by the log-rank test. RESULTS: Overall, 103 patients were enrolled (73 and 30 in the training and testing cohorts, respectively). The median follow-up was 38.1 months (interquartile range: 26.9, 49.4). The radiomic model had an area under the curve (AUC) of 0.983 in the training cohort and 0.814 in the testing cohort. Using a cut-off of 0.679 defined by the receiver operating characteristic (ROC) curve, patients with a high radiomic score (RS) had a higher risk for lung metastasis (HR 3.565, 95% CI 1.337, 9.505, p = 0.011), showing similar predictive performances for the mutant and wild-type KRAS groups (HR 3.225, 95% CI 1.249, 8.323, p = 0.016, IDI: 1.08%, p = 0.687; NRI 2.23%, p = 0.766). CONCLUSIONS: We established and validated a radiomic model for predicting KRAS status in LARC. Patients with high RS experienced more lung metastases. The model could noninvasively detect KRAS status and may help individualize clinical decision-making.

Coral-like BaTiO3-Filled Polymeric Composites as Piezoelectric Nanogenerators for Movement Sensing.

Piezoelectric nanogenerators have prospective uses for generating mechanical energy and powering electronic devices due to their high output and flexible behavior. In this research, the synthesis of the three-dimensional coral-like BaTiO3 (CBT) and its filling into a polyvinylidene fluoride (PVDF) matrix to obtain composites with excellent energy harvesting properties are reported. The CBT-based PENG has a 163 V voltage and a 16.7 µA current at a frequency of 4 Hz with 50 N compression. Simulations show that the high local stresses in the CBT coral branch structure are the main reason for the improved performance. The piezoelectric nanogenerator showed good durability at 5000 cycles, and 50 commercial light-emitting diodes were turned on. The piezoelectric nanogenerator generates a voltage of 4.68-12 V to capture the energy generated by the ball falling from different heights and a voltage of ≈0.55 V to capture the mechanical energy of the ball's movement as it passes. This study suggests a CBT-based piezoelectric nanogenerator for potential use in piezoelectric sensors that has dramatically improved energy harvesting characteristics.

Fucoidan derived from Sargassum pallidum alleviates metabolism disorders associated with improvement of cardiac injury and oxidative stress in diabetic mice.

Type 2 diabetes mellitus (T2DM) and its complications have become a serious global health epidemic. Cardiovascular complications have considered as a major cause of high mortality in diabetic patients. Fucoidans from brown algae have diverse medicinal activities, however, few studies reported pharmacological activity of Sargassum. pallidum fucoidan (Sp-Fuc). Therefore, the aim of this study was to investigate the effects of Sp-Fuc on diabetic symptoms and cardiac injury in spontaneous diabetic db/db mice. SP-Fuc at 200 mg/(kg/d) was administered intragastrically to db/db mice for 8 weeks, the effects on hyperlipidemia, hyperglycemia, insulin resistance, and cardiac damage, as well as oxidative stress, inflammation, Nrf2/ARE, and NF-κB signaling pathways, were investigated. Our data demonstrated that Sp-Fuc significantly (p < 0.05) decreased body weights, hyperlipidemia, and hyperglycemia in db/db mice, along with improved insulin sensitivity. Additionally, Sp-Fuc significantly (p < 0.05) alleviated cardiac dysfunction and pathological morphology of cardiac tissue. Sp-Fuc also significantly (p < 0.05) decreased lipid peroxidation, increased antioxidant function, as well as reduced cardiac inflammation, possibly through Nrf2/ARE and NF-κB signaling. Sp-Fuc can ameliorate the metabolism disorders of glucose and lipid in diabetic mice by activating Nrf2/ARE antioxidant signaling, simultaneously reducing cardiac redox imbalance and inflammatory damage. The present findings provide a perspective on the therapy strategy for T2DM and its complications.

MRI-based radiomics to predict neoadjuvant chemoradiotherapy outcomes in locally advanced rectal cancer: A multicenter study.

Background and purpose: Predicting tumour response would be useful for selecting patients with locally advanced rectal cancer (LARC) for organ preservation strategies. We aimed to develop and validate a prediction model for T downstaging (ypT0-2) in LARC patients after neoadjuvant chemoradiotherapy and to identify those who may benefit from consolidation chemotherapy. Materials and methods: cT3-4 LARC patients at three tertiary medical centers from January 2012 to January 2019 were retrospectively included, while a prospective cohort was recruited from June 2021 to March 2022. Eight filter (principal component analysis, least absolute shrinkage and selection operator, partial least-squares discriminant analysis, random forest)-classifier (support vector machine, logistic regression) models were established to select radiomic features. A nomogram combining radiomics and significant clinical features was developed and validated by calibration curve and decision curve analysis. Interaction test was conducted to investigate the consolidation chemotherapy benefits. Results: A total of 634 patients were included (426 in training cohort, 174 in testing cohort and 34 in prospective cohort). A radiomic prediction model using partial least-squares discriminant analysis and a support vector machine showed the best performance (AUC: 0.832 [training]; 0.763 [testing]). A nomogram combining radiomics and clinical features showed significantly better prognostic performance (AUC: 0.842 [training]; 0.809 [testing]) than the radiomic model. The model was also tested in the prospective cohort with AUC 0.727. High-probability group (score > 81.82) may have potential benefits from ≥ 4 cycles consolidation chemotherapy (OR: 4.173, 95 % CI: 0.953-18.276, p = 0.058, pinteraction = 0.021). Conclusion: We identified and validated a model based on multicenter pre-treatment radiomics to predict ypT0-2 in cT3-4 LARC patients, which may facilitate individualised treatment decision-making for organ-preservation strategies and consolidation chemotherapy.

Characterization of the complete chloroplast genome of Clematoclethra scandens subsp. actinidioides (Actinidiaceae).

Clematoclethra scandens subsp. actinidioides (Actinidiaceae) is an endemic medicinal species in China. Here, we first sequenced and characterized the complete chloroplast genome of C. scandens subsp. actinidioides. The chloroplast genome was 159,341 bp in length, containing a large single-copy of 88,351 bp and a small single-copy of 21,580 bp separated by a pair of identical inverted repeat regions of 24,705 bp each. A total of 131 genes were identified, including 84 protein-coding genes, 39 tRNA, and eight rRNA genes. The phylogenetic analysis of C. scandens subsp. actinidioides showed a relatively close relationship with Clematoclethra scandens subsp. hemsleyi.

CEP63 upregulates YAP1 to promote colorectal cancer progression through stabilizing RNA binding protein FXR1.

Abnormal regulation of centrosome components can induce chromosome instability and tumorigenesis. Centrosomal protein 63 (CEP63) is a vital member for assembling centrosome. Yet, the involvement of CEP63 in cancer pathogenesis remains unclear. Here we identify CEP63 as an important mediator for RNA-binding proteins (RBPs) to facilitate regulation on their RNA targets in colorectal cancer (CRC). We demonstrate that CEP63 protein is upregulated in a large cohort of colorectal cancer tissues and predicts poor prognosis, and USP36 is identified for stabilizing CEP63 by enhancing its K48-dependent deubiquitination. CEP63 overexpression promotes the proliferation and tumor growth of CRC cells in vitro and in vivo. Furthermore, we find that CEP63 can promote cancer stem-like cell properties by enhancing YAP1 expression through binding with and inhibiting the K63-ubiquitylation degradation of RBP FXR1 in CRC cells. Importantly, we further verify that the KH domain of FXR1 is necessary for the interaction between CEP63 and FXR1. Moreover, microtube motor proteins can form a complex with CEP63 and FXR1 to mediate the regulation of FXR1 on RNA targets. Additionally, we also confirm that CEP63 can bind and regulate multiple RBPs. In conclusion, our findings unveil an unrecognized CEP63/RBPs/RNA axis that CEP63 may perform as an adapter facilitating the formation of RBPs complex to regulate RNA progression and discover the role of CEP63 involved in signal transduction and RNA regulation, providing potential therapeutic target for CRC patients.

Revisiting sea-level budget by considering all potential impact factors for global mean sea-level change estimation.

Accurate estimates of global sea-level change from the observations of Altimetry, Argo and Gravity Recovery and Climate Experiment (GRACE) and GRACE Follow-on (GRACE-FO) are of great value for investigating the global sea-level budget. In this study, we analyzed the global sea-level change over the period from January 2005 to December 2019 by considering all potential impact factors, i.e. three factors for Altimetry observations (two Altimetry products, ocean bottom deformation (OBD) and glacial isostatic adjustment (GIA)), three factors for Argo observations (four Argo products, salinity product error and deep-ocean steric sea-level change), and seven factors for GRACE/GRACE-FO observations including three official RL06 solutions, five spatial filtering methods, three GIA models, two C20 (degree 2 order 0) products, Geocenter motion, GAD field and global mass conservation. The seven impact factors of GRACE/GRACE-FO observations lead to ninety combinations for the post-procession of global mean barystatic sea-level change estimation, whose rates range from 2.00 to 2.45 mm/year. The total uncertainty of global barystatic sea-level change rate is ± 0.27 mm/year at the 95% confidence level, estimated as the standard deviation of the differences between the different datasets constituting the ensembles. The statistical results show that the preferred GIA model developed by Caron et al. in 2018 can improve the closure of the global sea-level budget by 0.20-0.30 mm/year, which is comparable with that of neglecting the halosteric component. About 30.8% of total combinations (GRACE/GRACE-FO plus Argo) can close the global sea-level budget within 1-sigma (0.23 mm/year) of Altimetry observations, 88.9% within 2-sigma. Once the adopted factors including GRACE/GRACE-FO solutions from Center for Space Research (CSR), Caron18 GIA model, SWENSON filtering and Argo product from China Second Institute of Oceanography, the linear trend of global sterodynamic sea-level change derived from GRACE/GRACE-FO plus Argo observations is 3.85 ± 0.14 mm/year, nearly closed to 3.90 ± 0.23 mm/year of Altimetry observations.

Concurrent chemoradiotherapy using gemcitabine and nedaplatin in recurrent or locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Patients with recurrent or locally advanced head and neck squamous cell carcinoma (HNSCC) typically have limited treatment options and poor prognosis. AIM: To evaluate the efficacy and safety of two drugs with potent radio-sensitization properties including gemcitabine and nedaplatin as concurrent chemoradiotherapy regimens in treating HNSCC. METHODS: This single-arm prospective study enrolled patients with HNSCC to receive gemcitabine on days 1 and 8 and nedaplatin on days 1 to 3 for 21 days. Intensity-modulated radiation therapy with a conventional fraction was delivered 5 days per week. Objective response rate (ORR), disease control rate, and toxicity were observed as primary endpoints. Overall survival (OS) and progression free survival were recorded and analyzed as secondary endpoints. RESULTS: A total of 24 patients with HNSCC were enrolled. During the median 22.4-mo follow-up, both ORR and disease control rate were 100%. The one-year OS was 75%, and one-year progression-free survival (PFS) was 66.7% (median PFS was 15.1 mo). Recurrent HNSCC patients had a poorer prognosis than the treatment-naïve patients, and patients who achieved complete response had better survival than those in the PR group (all P < 0.05). The most common grade 1-4 (100%) or grade 3-4 toxicities (75%) were hematological, and the most common grade 3-4 non-hematological toxicity was mucositis in 17 (71%) patients. CONCLUSION: Gemcitabine plus nedaplatin with concurrent chemoradiotherapy is a therapeutic option for HNSCC with predictable tolerability. Considering the high adverse event rate, the optimized dose and schedule must be further explored.

KLF16 enhances stress tolerance of colorectal carcinomas by modulating nucleolar homeostasis and translational reprogramming.

Translational reprogramming is part of the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress, which acts to the advantage of cancer growth and development in different stress conditions, but the mechanism of ER stress-related translational reprogramming in colorectal carcinoma (CRC) progression remains unclear. Here, we identified that Krüppel-like factor 16 (KLF16) can promote CRC progression and stress tolerance through translational reprogramming. The expression of KLF16 was upregulated in CRC tissues and associated with poor prognosis for CRC patients. We found that ER stress inducers can recruit KLF16 to the nucleolus and increase its interaction with two essential proteins for nucleolar homeostasis: nucleophosmin1 (NPM1) and fibrillarin (FBL). Moreover, knockdown of KLF16 can dysregulate nucleolar homeostasis in CRC cells. Translation-reporter system and polysome profiling assays further showed that KLF16 can effectively promote cap-independent translation of ATF4, which can enhance ER-phagy and the proliferation of CRC cells. Overall, our study unveils a previously unrecognized role for KLF16 as an ER stress regulator through mediating translational reprogramming to enhance the stress tolerance of CRC cells and provides a potential therapeutic vulnerability.

A novel peptide encoded by N6-methyladenosine modified circMAP3K4 prevents apoptosis in hepatocellular carcinoma.

BACKGROUND: Circular RNAs (circRNAs) regulate various biological activities and have been shown to play crucial roles in hepatocellular carcinoma (HCC) progression. However, only a few coding circRNAs have been identified in cancers, and their roles in HCC remain elusive. This study aimed to identify coding circRNAs and explore their function in HCC. METHODS: CircMAP3K4 was selected from the CIRCpedia database. We performed a series of experiments to determine the characteristics and coding capacity of circMAP3K4. We then used in vivo and in vitro assays to investigate the biological function and mechanism of circMAP3K4 and its protein product, circMAP3K4-455aa, in HCC. RESULTS: We found circMAP3K4 to be an upregulated circRNA with coding potential in HCC. IGF2BP1 recognized the circMAP3K4 N6-methyladenosine modification and promoted its translation into circMAP3K4-455aa. Functionally, circMAP3K4-455aa prevented cisplatin-induced apoptosis in HCC cells by interacting with AIF, thus protecting AIF from cleavage and decreasing its nuclear distribution. Moreover, circMAP3K4-455aa was degraded through the ubiquitin-proteasome E3 ligase MIB1 pathway. Clinically, a high level of circMAP3K4 is an independent prognostic factor for adverse overall survival and adverse disease-free survival of HCC patients. CONCLUSIONS: CircMAP3K4 is a highly expressed circRNA in HCC. Driven by m6A modification, circMAP3K4 encoded circMAP3K4-455aa, protected HCC cells from cisplatin exposure, and predicted worse prognosis of HCC patients. Targeting circMAP3K4-455aa may provide a new therapeutic strategy for HCC patients, especially for those with chemoresistance. CircMAP3K4 is a highly expressed circRNA in HCC. Driven by m6A modification, IGF2BP1 facilitates circMAP3K4 peptide translation, then the circMAP3K4 peptide inhibits AIF cleavage and nuclear distribution, preventing HCC cells from cell death under stress and promoting HCC progression.

MRI radiomics independent of clinical baseline characteristics and neoadjuvant treatment modalities predicts response to neoadjuvant therapy in rectal cancer.

BACKGROUND: To analyse the performance of multicentre pre-treatment MRI-based radiomics (MBR) signatures combined with clinical baseline characteristics and neoadjuvant treatment modalities to predict complete response to neoadjuvant (chemo)radiotherapy in locally advanced rectal cancer (LARC). METHODS: Baseline MRI and clinical characteristics with neoadjuvant treatment modalities at four centres were collected. Decision tree, support vector machine and five-fold cross-validation were applied for two non-imaging and three radiomics-based models' development and validation. RESULTS: We finally included 674 patients. Pre-treatment CEA, T stage, and histologic grade were selected to generate two non-imaging models: C model (clinical baseline characteristics alone) and CT model (clinical baseline characteristics combining neoadjuvant treatment modalities). The prediction performance of both non-imaging models were poor. The MBR signatures comprising 30 selected radiomics features, the MBR signatures combining clinical baseline characteristics (CMBR), and the CMBR incorporating neoadjuvant treatment modalities (CTMBR) all showed good discrimination with mean AUCs of 0.7835, 0.7871 and 0.7916 in validation sets, respectively. The three radiomics-based models had insignificant discrimination in performance. CONCLUSIONS: The performance of the radiomics-based models were superior to the non-imaging models. MBR signatures seemed to reflect LARC's true nature more accurately than clinical parameters and helped identify patients who can undergo organ preservation strategies.

TBX20 inhibits colorectal cancer tumorigenesis by impairing NHEJ-mediated DNA repair.

DNA high methylation is one of driving force for colorectal carcinoma (CRC) pathogenesis. Transcription factors (TFs) can determine cell fate and play fundamental roles in multistep process of tumorigenesis. Dysregulation of DNA methylation of TFs should be vital for the progression of CRC. Here, we demonstrated that TBX20, a T-box TF family protein, was downregulated with hypermethylation of promoter in early-stage CRC tissues and correlated with a poor prognosis for CRC patients. Moreover, we identified PDZRN3 as the E3 ubiquitin ligase of TBX20 protein, which mediated the ubiquitination and degradation of TBX20. Furthermore, we revealed that TBX20 suppressed cell proliferation and tumor growth through impairing non-homologous DNA end joining (NHEJ)-mediated double-stranded break repair by binding the middle domain of both Ku70 and Ku80 and therefore inhibiting their recruitment on chromatin in CRC cells. Altogether, our results reveal the tumor-suppressive role of TBX20 by inhibiting NHEJ-mediated DNA repair in CRC cells, and provide a potential biomarker for predicting the prognosis of patients with early-stage CRC and a therapeutic target for combination therapy.