Excessive cadmium (Cd) accumulation in grains of rice (Oryza sativa L.) is a risk to food security. The transporters in the nodes of rice are involved in the distribution of mineral elements including toxic elements to different tissues such as grains. However, the mechanism of Cd accumulation in grains is largely unknown. Here, we report a node-expressed transporter gene, OsCCX2, a putative cation/calcium (Ca) exchanger, mediating Cd accumulation in the grains of rice. Knockout of OsCCX2 caused a remarkable reduction of Cd content in the grains. Further study showed that disruption of this gene led to a reduced root-to-shoot translocation ratio of Cd. Moreover, Cd distribution was also disturbed in different levels of internode and leaf. OsCCX2 is localized to plasma membrane, and OsCCX2 is mainly expressed in xylem region of vascular tissues at the nodes. OsCCX2 might function as an efflux transporter, responsible for Cd loading into xylem vessels. Therefore, our finding revealed a novel Cd transporter involved in grain Cd accumulation, possibly via a Ca transport pathway in the nodes of rice.

BackgroundTriple-negative breast cancer (TNBC) is associated with an aggressive clinical course due to the lack of therapeutic targets. Therefore, identifying reliable prognostic biomarkers and novel therapeutic targets for patients with TNBC is required. Proline, glutamic acid, leucine rich protein 1 (PELP1) is a novel steroidal receptor co-regulator, functioning as an oncogene and its expression is maintained in estrogen receptor (ER) negative breast cancers. PELP1 has been proposed as a prognostic biomarker in hormone-related cancers, including luminal-type breast cancers, but its significance in TNBC has not been studied.MethodsPELP1 immunoreactivity was evaluated using immunohistochemistry in 129 patients with TNBC. Results were correlated with clinicopathological variables including patient’s age, tumor size, lymph node stage, tumor grade, clinical stage, histological type, Ki-67 LI, as well as clinical outcome of the patients, including disease-free survival (DFS) and overall survival (OS).ResultsPELP1 was localized predominantly in the nuclei of carcinoma cells in TNBC. With the exception of a positive correlation between PELP1 protein expression and lymph node stage (p = 0.027), no significant associations between PELP1 protein expression and other clinicopathological variables, including DFS and OS, were found. However, when PELP1 and Ki-67 LI were grouped together, we found that patients in the PELP1/Ki-67 double high group (n = 48) demonstrated significantly reduced DFS (p = 0.005, log rank test) and OS (p = 0.002, log rank test) than others (n = 81). Multivariable analysis supported PELP1/Ki-67 double high expression as an independent prognostic factor in patients with TNBC, with an adjusted hazard ratio of 2.020 for recurrence (95 % CL, 1.022–3.990; p = 0.043) and of 2.380 for death (95 % CL, 1.138–4.978; p = 0.021).ConclusionsWe found that evaluating both PELP1 and Ki-67 expression in TNBC could enhance the prognostic sensitivity of the two biomarkers. Therefore, we propose that PELP1/Ki-67 double high expression in tumors is an independent prognostic factor for predicting a poor outcome for patients with TNBC.

Myostatin (MSTN), associated with the “double muscling” phenotype, affects muscle growth and fat deposition in animals, whereas how MSTN affects adipogenesis remains to be discovered. Here we show that MSTN can act through the MEF2C/miR222/SCD5 cascade to regulate fatty acid metabolism. We generated MSTN-knockout (KO) cloned Meishan pigs, which exhibits typical double muscling trait. We then sequenced transcriptome of subcutaneous fat tissues of wild-type (WT) and MSTN-KO pigs, and intersected the differentially expressed mRNAs and miRNAs to predict that stearoyl-CoA desaturase 5 (SCD5) is targeted by miR222. Transcription factor binding prediction showed that myogenic transcription factor 2C (MEF2C) potentially binds to the miR222 promoter. We hypothesized that MSTN-KO upregulates MEF2C and consequently increases the miR222 expression, which in turn targets SCD5 to suppress its translation. Biochemical, molecular and cellular experiments verified the existence of the cascade. This novel molecular pathway sheds light on new targets for genetic improvements in pigs.

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment prolongs the survival of lung cancer patients harbouring activating EGFR mutations. However, resistance to EGFR-TKIs is inevitable after long-term treatment. Molecular mechanistic research is of great importance in combatting resistance. A comprehensive investigation of the molecular mechanisms underlying resistance has important implications for overcoming resistance. An accumulating body of evidence shows that lncRNAs can contribute to tumorigenesis and treatment resistance. By bioinformatics analysis, we found that LINC00969 expression was elevated in lung cancer cells with acquired gefitinib resistance. LINC00969 regulated resistance to gefitinib in vitro and in vivo. Mechanistically, gain of H3K4me1 and H3K27Ac led to the activation of LINC00969 expression. LINC00969 interacts with EZH2 and METTL3, transcriptionally regulates the level of H3K27me3 in the NLRP3 promoter region, and posttranscriptionally modifies the m6A level of NLRP3 in an m6A-YTHDF2-dependent manner, thus epigenetically repressing NLRP3 expression to suppress the activation of the NLRP3/caspase-1/GSDMD-related classical pyroptosis signalling pathways, thereby endowing an antipyroptotic phenotype and promoting TKI resistance in lung cancer. Our findings provide a new mechanism for lncRNA-mediated TKI resistance from the new perspective of pyroptosis via simultaneous regulation of histone methylation and RNA methylation. The pivotal role of LINC00969 gives it the potential to be a novel biomarker and therapeutic target for overcoming EGFR-TKI resistance in lung cancer.

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Background: Circulating tumor cells and serum tumor markers have been found significant in predicting outcome for several malignancies. However, their role in gastric cancer is not fully clarified. We conducted a retrospective study to explore the prognostic value of circulating tumor cells and their applicability in assessing the treatment efficacy in gastric cancers. Methods: From September 2015 to December 2018, 116 patients with newly pathologically diagnosed gastric adenocarcinoma were enrolled. At both baseline and two courses after chemotherapy, the data of circulating tumor cells and serum tumor markers, such as CEA, CA72-4, CA19-9, CA50, and CA242, were collected. The relationships between the change trend of circulating tumor cells and the treatment efficacy were analyzed after chemotherapy, with a paired t-test. Univariate and multivariable analysis were used to find prognostic factors for overall survival (OS). Results: We found there is a significant difference between the circulating tumor cells-positive and circulating tumor cells-negative before and after therapy (mOS 12.6 vs. 31.6 months, P<0.001; mOS 12.4 vs. 24.2 months, P=0.002), respectively. Also, differentiation, pre-therapeutic circulating tumor cells and therapeutic response were independent predictors of overall survival. Following two courses of chemotherapy, the number of circulating tumor cells increased obviously in the progressive disease group ( P=0.002), while they decreased in the non-progressive disease group ( P=0.02). Thus, the change in the circulating tumor cells count had a close association with the therapeutic response ( P=0.004). Conclusion: Generally, circulating tumor cells provide a novel tool to evaluate the outcomes of gastric cancer patients. Since the change of circulating tumor cells was highly related to treatment response, it may be an auxiliary to assess the effect of chemotherapy, leading an earlier adjustment of following regimens.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI, such as gefitinib) in lung cancer continues to be a major problem. Recent studies have shown the promise of ferroptosis-inducing therapy in EGFR-TKI resistant cancer, but have not been translated into clinical benefits. Here, we identified carbonic anhydrase IX (CA9) was upregulated in gefitinib-resistant lung cancer. Then we measured the cell viability, intracellular reactive oxygen species (ROS) levels, and labile iron levels after the treatment of ferroptosis inducer erastin. We found that CA9 confers resistance to ferroptosis-inducing drugs. Mechanistically, CA9 is involved in the inhibition of transferrin endocytosis and the stabilization of ferritin, leading to resistance to ferroptosis. Targeting CA9 promotes iron uptake and release, thus triggering gefitinib-resistant cell ferroptosis. Notably, CA9 inhibitor enhances the ferroptosis-inducing effect of cisplatin on gefitinib-resistant cells, thus eliminating resistant cells in heterogeneous tumor tissues. Taken together, CA9-targeting therapy is a promising approach to improve the therapeutic effect of gefitinib-resistant lung cancer by inducing ferroptosis.

Background: IKBKB/IKKβ, as the core catalytic subunit of IκB kinase complex, participates in mediation of the classical NF-κB pathway, which has been linked to inflammation and tumorigenesis. Previous studies have shown that single nucleotide polymorphisms in IKBKB have been related to gastric cancer, but how they associate to the clinical outcome is not yet clear. In this study, we retrospectively investigated the associations between single nucleotide polymorphisms located in IKBKB and gastric cancer survival. Materials and Methods: IKBKB rs2272736 was genotyped in 1210 patients with primary gastric cancer in a Han Chinese population, and the relationships between rs2272736 and overall survival were evaluated. We conducted Cox proportional hazards regression, which was performed to estimate the effects of single nucleotide polymorphisms on the overall survival of patients, adjusted for potential confounding variables. Results: We found that patients with rs2272736 A allele in IKBKB had significantly prolonged overall survival time compared to those with the G allele (HR = 0.83, 95% CI = 0.68-1.00, P = 0.050). In addition, AA genotype was demonstrated to have reduced risk of death for gastric cancer compared with that associated with the GG/GA genotypes, which was more common in patients with cardiac carcinoma, well-differentiated and moderately differentiated tumors, TNM Ⅰ/Ⅱ stages and intestinal type. Conclusion: Our findings have shown that single nucleotide polymorphism rs2272736 in IKBKB may be a promising prognostic biomarker which should promote personalized treatment.