Exosomal circPACRGL promotes progression of colorectal cancer via the miR-142-3p/miR-506-3p- TGF-ß1 axis.

BACKGROUND: Colorectal cancer (CRC) is the leading cause of cancer-related death worldwide. Exosome shave emerged as crucial regulators of intercellular communication and that abundant Circular RNAs (circRNAs) are enriched within exosomes. CircRNAs are novel members of noncoding RNAs regulating cancer proliferation and progression. However, the function and regulatory mechanism of cancer-derived exosomal circRNAs in CRC remains unclear. METHODS: CRC cells-derived exosomes were characterized using transmission electron microscopy, nanoparticle tracking analysis (NTA) and western blot. CCK-8, wound healing and transwell assays, and flow cytometry assays were conducted to assess whether exosomes would affect the proliferation, metastasis, and apoptosis of CRC cells, respectively. Moreover, we performed the RNA sequencing and RT-qPCR to identify circRNAs in exosome-stimulated CRC cells. Fluorescence in situ hybridization (FISH) assay was used to detect the cellular distribution of circPACRGL. Bioinformatic analyses (StarBase 2.0) were used to pool the miRNA targets of circPACRGL. Luciferase assays were performed to verify the direct interaction. Finally, flow cytometry was used to detect the differentiation of N1-N2 neutrophils. RESULTS: Our study identified a novel CRC-derived exosomal circRNA, circPACRGL. We found circPACRGL was significantly upregulated in CRC cells after tumor-derived exosomes addition. Moreover, circPACRGL serves as a sponge for miR-142-3p/miR-506-3p to facilitate the transforming growth factor-ß1 (TGF-ß1) expression. As a result, circPACRGL promoted CRC cell proliferation, migration and invasion, as well as differentiation of N1 to N2 neutrophils via miR-142-3p/miR-506-3p-TGF-ß1 axis. CONCLUSION: Our study, the first to reveal that cancer-derived exosomal circPACRGL plays an oncogenic role in CRC proliferation and metastasis, providing mechanistic insights into the roles of circRNAs in CRC progression and a valuable marker for CRC treatment.

Exosomal KRAS mutation promotes the formation of tumor-associated neutrophil extracellular traps and causes deterioration of colorectal cancer by inducing IL-8 expression.

BACKGROUND: Colorectal cancer (CRC) remains one of the leading causes of cancer-related death. The current study aimed to elucidate the mechanism by which exosomes carrying KRAS mutant contribute to neutrophil recruitment as well as the formation of the neutrophil extracellular trap (NET) in CRC. METHODS: APC-WT and APC-KRASG12D mouse models were initially developed. Peripheral blood, spleen, bone marrow (BM) and mesenteric lymph nodes (mLN) were isolated to detect neutrophil content. Then, APC-WT and APC-KRASG12D mice were injected with exosomes isolated from APC-WT and APC-KRASG12D mice. The ratio of neutrophils, NETs formation and IL-8 protein content were subsequently quantified in colon tissues. DKs-8 (wild type) and DKO-1 (KRAS mutant) cells were employed for in vitro experimentation. Then, DKs-8 cells were cultured with exosome-treated PMA stimulated neutrophil-forming NETs culture medium, with cell viability, invasion, migration, and adhesion evaluated. RESULTS: Compared with APC-WT mice, the numbers of polyps and neutrophils in the peripheral blood, spleen and mLNs were increased in APC-KRASG12D mice, accompanied with increased NET formation, IL-8 expression and exosomes. Meanwhile, IL-8 upregulation, neutrophil recruitment and NET formation were observed in the mice injected with exosomes derived from APC-KRASG12D. The in vitro investigation results revealed that more NETs were formed in the presence of DKO-1-Exos, which were inhibited by DNAse. In addition, DKs-8- and DKO-1 cells-derived exosomes could adhere to NETs under static conditions in vitro. Exosomal KRAS mutants were noted to exert stimulatory effects on the IL-8 production and NET formation to promote the growth of CRC cells. CONCLUSION: The results provide evidence suggesting that exosomes may transfer mutant KRAS to recipient cells and trigger increases in IL-8 production, neutrophil recruitment and formation of NETs, eventually leading to the deterioration of CRC.

FKF1 F-box protein promotes flowering in part by negatively regulating DELLA protein stability under long-day photoperiod in Arabidopsis.

FLAVIN-BINDING KELCH REPEAT F-BOX 1 (FKF1) encodes an F-box protein that regulates photoperiod flowering in Arabidopsis under long-day conditions (LDs). Gibberellin (GA) is also important for regulating flowering under LDs. However, how FKF1 and the GA pathway work in concert in regulating flowering is not fully understood. Here, we showed that the mutation of FKF1 could cause accumulation of DELLA proteins, which are crucial repressors in GA signaling pathway, thereby reducing plant sensitivity to GA in flowering. Both in vitro and in vivo biochemical analyses demonstrated that FKF1 directly interacted with DELLA proteins. Furthermore, we showed that FKF1 promoted ubiquitination and degradation of DELLA proteins. Analysis of genetic data revealed that FKF1 acted partially through DELLAs to regulate flowering under LDs. In addition, DELLAs exerted a negative feedback on FKF1 expression. Collectively, these findings demonstrate that FKF1 promotes flowering partially by negatively regulating DELLA protein stability under LDs, and suggesting a potential mechanism linking the FKF1 to the GA signaling DELLA proteins.

Knockdown of long noncoding RNA PVT1 suppresses cell proliferation and invasion of colorectal cancer via upregulation of microRNA-214-3p.

Long noncoding RNAs (lncRNAs) have been reported to be involved in the occurrence and tumorigenesis of numerous malignant cancers. Microarray expression profiles were used to screen colorectal cancer (CRC)-related differentially expressed genes and lncRNAs, which revealed that insulin receptor substrate 1 (IRS1) and lncRNA plasmacytoma variant translocation 1 (PVT1) were highly expressed in CRC. This study aimed to investigate the regulatory role of lncRNA PVT1 in CRC. Subcellular localization detected by fluorescence in situ hybridization identified that lncRNA PVT1 was primarily located in the cytoplasm. The interaction between lncRNA PVT1 and microRNA-214-3p (miR-214-3p) and IRS1 was predicted using the RNA22 website. Next the dual luciferase reporter gene assay, RNA pull-down, and RNA immunoprecipitation assays verified lncRNA PVT1 to be a competitive endogenous RNA (ceRNA) against miR-214-3p, and IRS1 was found to be a target of miR-214-3p. The expression pattern of lncRNA PVT1, miR-214-3p, IRS1, phosphoinositide 3-kinase (PI3K), and Akt was characterized in response to lncRNA PVT1 silencing or miR-214-3p upregulation. Meanwhile, their regulatory effects on cell proliferation, invasion, and apoptosis were detected in CRC cells. With increased levels of miR-214-3p and decreased levels of lncRNA PVT1 in CRC cells, the expression of phosphatidylinositol 3-kinase, putative (PI3K) and Akt was reduced, and consequently, the cell apoptosis was stimulated and cell proliferation and invasion were suppressed. All in all, lncRNA PVT1 competitively binds to miR-214-3p to upregulate the expression of IRS1 thus activating the PI3K/Akt signaling pathway, thus accelerating CRC progression. This study suggests that lncRNA PVT1 might be a potential target of therapeutic strategies for CRC treatment.NEW & NOTEWORTHY This study mainly suggests that long noncoding (lnc)RNA plasmacytoma variant translocation 1 (PVT1) is a downregulated lncRNA in colorectal cancer (CRC), accelerating CRC progression. Strikingly, lncRNA PVT1 acts as a competitive endogenous RNA against microRNA (miR)-214-3p, whereas miR-214-3p targets insulin receptor substrate 1, which draws a comprehensive picture of the potential molecular mechanisms of lncRNA PVT1 in CRC.

Liquid biopsy in lung cancer.

Lung cancer is a highly prevalent malignancy worldwide and the primary cause of mortality. The absence of systematic and standardized diagnostic approaches for identifying potential pulmonary nodules, early-stage cancers, and indeterminate tumors has led clinicians to consider tissue biopsy and pathological sections as the preferred method for clinical diagnosis, often regarded as the gold standard. The conventional tissue biopsy is an invasive procedure that does not adequately capture the diverse characteristics and evolving nature of tumors. Recently, the concept of 'liquid biopsy' has gained considerable attention as a promising solution. Liquid biopsy is a non-invasive approach that facilitates repeated analysis, enabling real-time monitoring of tumor recurrence, metastasis, and response to treatment. Currently, liquid biopsy includes circulating tumor cells, circulating cell-free DNA, circulating tumor DNA, circulating cell-free RNA, extracellular vesicles, and other proteins and metabolites. With rapid progress in molecular technology, liquid biopsy has emerged as a highly promising and intriguing approach, yielding compelling results. This article critically examines the significant role and potential clinical implications of liquid biopsy in the diagnosis, treatment, and prognosis of lung cancer.

N6-methyladenosine demethyltransferase FTO mediated m6A modification of estrogen receptor alpha in non-small cell lung cancer tumorigenesis.

Fat mass and obesity-associated protein (FTO), which is closely linked with obesity and dietary intake, plays an important role in diet-related metabolic diseases. However, the underlying mechanism of the N6-methyladenosine (m6A) demethyltransferase FTO in tumor development and progression remains largely unexplored. Here, we demonstrated that FTO expression was largely lower in non-small cell lung cancer (NSCLC) samples than in adjacent healthy tissues, and its expression negatively correlated with poor prognosis. Gain- and loss-of-function assays revealed that FTO inhibited NSCLC tumor cell growth and metastasis in vitro and in vivo. Mechanistically, estrogen receptor alpha (ESR1) is a target of FTO, and increased FTO expression significantly impaired the m6A levels of ESR1 mRNA. There were two clear m6A modification sites (5247A and 5409A) in the 3' untranslated region (3'UTR) of ESR1, and FTO could decrease their methylation. Moreover, the m6A readers YTHDF1 and IGF2BP3 recognized and bound the m6A sites in ESR1 mRNA, thereby enhancing its stability and facilitating tumor growth. We also showed that ESR1 has good diagnostic value for NSCLC. In conclusion, we uncovered an important mechanism of epitranscriptomic regulation by the FTO-YTHDF1-IGF2BP3-ESR1 axis and identified the potential of m6A-dependent therapeutic strategies for NSCLC.

Differences in serum cytokine levels distinguish between clinically noninvasive lung adenocarcinoma and invasive lung adenocarcinoma: A cross-sectional study.

Background: Lung cancer incidence and mortality remain high and are now the leading cause of cancer-related death. Lung adenocarcinoma (LUAD) is one of the main histological subtypes of lung cancer. Previous studies have shown the role of inflammation in the development of lung cancer, but the relationship between cytokines and LUAD is still unclear. To further differentiate and explore the association of cytokines with the risk of non-invasive and invasive LUAD, we studied and assessed serum cytokine levels in patients with two types of LUAD. Methods: A cohort study of 90 non-invasive LUAD and 90 invasive LUAD was retrospectively included, and the clinical characteristics were recorded in detail. The differences in the levels of 12 serum cytokines (IFN-α, IFN-γ, IL-10, IL-12P70, IL-17A, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, and TNF-α) between the two groups of patients with LUAD were analyzed and evaluated. And we evaluated the clinical value of cytokine differential diagnosis of invasive LUAD based on receiver operating characteristics (ROC) curves. Results: The mean age of the patients was 56.6 years, and the proportions of males and females were 38.9% and 61.1%, respectively. IFN-α, IL-1ß, IL-2, IL-6, TNF-α, IL-4, and IL-8 were significantly increased in patients with invasive LUAD compared with the non-invasive LUAD group. Further research found that smoking is an important factor, with changes in the four cytokines IL-1ß, IL-6, IL-8, and TNF-α being significantly higher in the smoking group of patients with invasive LUAD. It can be seen from the area under the curve that IL-1ß and IL-2 have a significant differential diagnosis. Conclusions: We observed differences in preoperative serum cytokine levels between patients with invasive and non-invasive LUAD, which may serve as potential serum biomarkers for clinical differential diagnosis and disease progression assessment.

Erratum: Myeloid cell-derived LL-37 promotes lung cancer growth by activating Wnt/ß-catenin signaling: Erratum.

[This corrects the article DOI: 10.7150/thno.30726.].

Integrated Clinical and Prognostic Analysis of the m6A RNA Methylation Regulator YTHDF3 in Pan-Cancer and its Correlation with Cancer Cell Proliferation.

Background: N6-methyladenosine (m6A) is the most abundant and extensive chemical modification of mammalian RNA molecules. Although numerous studies have investigated m6A methylation-related genes, to the best of our knowledge, none have examined the expression patterns of YTH N6-methyladenosine RNA binding protein 3 (YTHDF3) across cancers. Methods: Using various publicly available datasets, we searched for a potential carcinogenic role of YTHDF3 in 33 tumor types. Furthermore, the clinicopathological parameters, clinical prognostic value, enrichment analysis, mutations, microsatellite instability (MSI), tumor mutation burden (TMB), levels of infiltrating cells, and related immune checkpoint genes were included. Finally, we performed a validation analysis using existing clinical samples and proliferation-related functional experiments. Results: YTHDF3 is highly expressed in most cancer types and associated with patient prognosis in certain tumors. The ROC analysis suggested that YTHDF3 has high diagnostic value in 13 types of cancer. Furthermore, we found that the genes associated with YTHDF3 were enriched for translation initiation and mRNA metabolic processes. The results of the GSEA enrichment suggest that YTHDF3 may be associated with different pathways in cells in various tumor types. We further analyzed the correlations between YTHDF3 expression and MSI, TMB, and immune checkpoint genes. YTHDF3 also possibly exerts important antitumor immunotherapy effects. Additionally, the results of the immune analysis using TIMER showed that high YTHDF3 expression levels in pan-cancer tissues were related to an immunosuppressive microenvironment. Finally, we experimentally demonstrated that both overexpression and downregulation of YTHDF3 can affect cancer cell proliferation rates. Conclusion: YTHDF3 is a promising biomarker for cancer diagnosis. This study provides the first comprehensive pan-cancer report on YTHDF3 and increases our understanding of its oncogenic role in different tumors.

N6-Methyladenosine-Regulated mRNAs: Potential Prognostic Biomarkers for Patients With Lung Adenocarcinoma.

Aberrant regulation of m6A mRNA modification can lead to changes in gene expression, thus contributing to tumorigenesis in several types of solid tumors. In this study, by integrating analyses of m6A methylation and mRNA expression, we identified 84 m6A-regulated mRNAs in lung adenocarcinoma (LUAD). Although the m6A methylation levels of total RNA in LUAD patient tumor tissue were reduced, the majority (75.2%) of m6A-regulated mRNAs were hypermethylated. The m6A-hypermethylated mRNAs were mainly enriched in terms related to transcription factor activity. We established a 10-m6A-regulated-mRNA signature score system through least absolute shrinkage and selection operator Cox regression analysis, with its predictive value validated by Kaplan-Meier curve and time-dependent receiver operating characteristic curves. RFXAP and KHDRBS2 from the signature also exhibited an independent prognostic value. The co-expression and interaction network analyses demonstrated the strong correlation between m6A regulators and the genes in the signature, further supporting the results of the m6A methylation modification patterns. These findings highlight the potential utility of integrating multi-omics data (m6A methylation level and mRNA expression) to accurately obtain potential prognostic biomarkers, which may provide important insights into developing novel and effective therapies for LUAD.

The blue light receptor CRY1 interacts with GID1 and DELLA proteins to repress GA signaling during photomorphogenesis in Arabidopsis.

Light is a critical environmental cue that regulates a variety of diverse plant developmental processes. Cryptochrome 1 (CRY1) is the major photoreceptor that mediates blue light-dependent photomorphogenic responses such as the inhibition of hypocotyl elongation. Gibberellin (GA) participates in the repression of photomorphogenesis and promotes hypocotyl elongation. However, the antagonistic interaction between blue light and GA is not well understood. Here, we report that blue light represses GA-induced degradation of the DELLA proteins (DELLAs), which are key negative regulators in the GA signaling pathway, via CRY1, thereby inhibiting the GA response during hypocotyl elongation. Both in vitro and in vivo biochemical analyses demonstrated that CRY1 physically interacts with GA receptors-GA-INSENSITIVE DWARF 1 proteins (GID1s)-and DELLAs in a blue light-dependent manner. Furthermore, we showed that CRY1 inhibits the association between GID1s and DELLAs. Genetically, CRY1 antagonizes the function of GID1s to repress the expression of cell elongation-related genes and thus hypocotyl elongation. Taken together, our findings demonstrate that CRY1 coordinates blue light and GA signaling for plant photomorphogenesis by stabilizing DELLAs through the binding and inactivation of GID1s, providing new insights into the mechanism by which blue light antagonizes the function of GA in photomorphogenesis.

A nomogram from the SEER database for predicting the prognosis of patients with non-small cell lung cancer.

OBJECTIVE: The purpose of this study was to establish and validate a nomogram to predict the prognosis in patients with non-small cell lung cancer (NSCLC) from multiple perspectives. RESULTS: A total of 98,640 eligible patients were randomly divided into a training set (n = 69,048) and a validation set (n = 29,592). The baseline characteristics of the two sets were similar. We used clinical data from patients in the training set for univariate and multivariate Cox regression analyses. Twelve independent risk factors were incorporated for constructed a prognostic nomogram. And the nomogram with a concordance index of 0.777 (95 % CI, 0.775 to 0.779) for overall survival. The calibration curve results showed that the actual survival rate was consistent with the predicted survival rate. The area under curve of the receiver operating characteristic curves demonstrated that the nomogram has a high prediction of the overall survival rate in patients with NSCLC. CONCLUSION: We have developed a nomogram with high prediction accuracy and discrimination ability, which can help clinicians making personalized survival predictions for NSCLC patients.

Correction to: Long non-coding RNA HOTTIP enhances IL-6 expression to potentiate immune escape of ovarian cancer cells by upregulating the expression of PD-L1 in neutrophils.

An amendment to this paper has been published and can be accessed via the original article.

Exosomal miR-183-5p promotes angiogenesis in colorectal cancer by regulation of FOXO1.

Exosomes play important roles in proliferation and microenvironment modulation of many types of cancers, including colorectal cancer (CRC). However, the inhibitory effect of CRC cells-derived exosomes in angiogenesis has not been fully discussed. In this study, the roles of microRNA-183-5p (miR-183-5p) in abundant in exosomes secreted from the CRC cells were investigated. Initially, microarray analysis was employed to determine the differentially expressed miRNAs. Exosomes isolated from CRC cells were co-cultured with HMEC-1 cells to explore the role of exosomes in angiogenesis. Further, the effects of CRC cell-derived exosomal miR-183-5p on proliferation, invasion and tube formation abilities of HMEC-1 cells were assessed. The preventative effect of exosomal miR-183-5p in vivo was measured in nude mice. Initially, it was found that FOXO1 was downregulated while miR-183-5p was upregulated in CRC. Additionally, the inhibition of miR-183-5p was suggested to suppress proliferation, invasion and tube formation abilities of HMEC-1 cells through upregulating FOXO1. Then, in vitro assays demonstrated that CRC cell-derived exosomes overexpressing miR-183-5p contributed to an enhanced proliferation, invasion and tube formation abilities of HMEC-1 cells. Furthermore, in vivo experiments confirmed the tumor-promotive effects of CRC cell-derived exosomal miR-183-5p. Collectively, our study demonstrates that the CRC cell-derived exosomes overexpressing miR-183-5p aggravates CRC through the regulation of FOXO1. Exosomes overexpressing miR-183-5p might be a potential treatment biomarker for CRC.

Long non-coding RNA HOTTIP enhances IL-6 expression to potentiate immune escape of ovarian cancer cells by upregulating the expression of PD-L1 in neutrophils.

BACKGROUND: Long non-coding RNA (lncRNA) HOXA transcript at the distal tip (HOTTIP), has been demonstrated to be a vital biomarker when evaluating the prognosis of multiple cancers. Nevertheless, the potential function of HOTTIP in ovarian cancer (OC), a prevalent cancer among women worldwide, remains elusive. Hence, the current study aimed to elucidate the functional relevance of HOTTIP in the development of OC. METHODS: Positive expression of PD-L1 and IL-6 was determined using immunohistochemical staining in the collected OC and normal tissues. The correlation of IL-6 and PD-L1 was analyzed using flow cytometry, Western blot analysis as well as Pearson's correlation coefficient. The interaction among HOTTIP, c-jun and IL-6 was investigated with the use of RIP, ChIP and dual luciferase reporter gene assays. Finally, the effects of HOTTIP on T cell proliferation and infiltration were identified through gain- and loss-of-function studies in vitro and in vivo. RESULTS: HOTTIP, IL-6 and PD-L1 were all highly expressed in OC tissues. A positive correlation was observed between IL-6 and PD-L1 and that between HOTTIP and IL-6 in OC tissues. HOTTIP was noted to promote the expression of IL-6 by binding to c-jun, which resulted in a promoted PD-L1 expression in neutrophils and immune escape while inhibiting T cell proliferation as well as tumor immunotherapy. CONCLUSION: Taken together, our study unveiled that HOTTIP could promote the secretion of IL-6, and consequently up-regulate the expression of PD-L1 in neutrophils, thus inhibiting the activity of T cells and ultimately accelerating immune escape of OC cells. Our study provides a potential therapeutic strategy by targeting HOTTIP in OC.

Myeloid cell-derived LL-37 promotes lung cancer growth by activating Wnt/ß-catenin signaling.

Rationale: Antimicrobial peptides, such as cathelicidin LL-37/hCAP-18, are important effectors of the innate immune system with direct antibacterial activity. In addition, LL-37 is involved in the regulation of tumor cell growth. However, the molecular mechanisms underlying the functions of LL-37 in promoting lung cancer are not fully understood. Methods: The expression of LL-37 in the tissues and sera of patients with non-small cell lung cancer was determined through immunohistological, immunofluorescence analysis, and enzyme-linked immunosorbent assay. The animal model of wild-type and Cramp knockout mice was employed to evaluate the tumorigenic effect of LL-37 in non-small cell lung cancer. The mechanism of LL-37 involving in the promotion of lung tumor growth was evaluated via microarray analyses, recombinant protein treatment approaches in vitro, tumor immunohistochemical assays, and intervention studies in vivo. Results: LL-37 produced by myeloid cells was frequently upregulated in primary human lung cancer tissues. Moreover, its expression level correlated with poor clinical outcome. LL-37 activated Wnt/ß-catenin signaling by inducing the phosphorylation of protein kinase B and subsequent phosphorylation of glycogen synthase kinase 3ß mediated by the toll-like receptor-4 expressed in lung tumor cells. LL-37 treatment of tumor cells also decreased the levels of Axin2. In contrast, it elevated those of an RNA-binding protein (tristetraprolin), which may be involved in the mechanism through which LL-37 induces activation of Wnt/ß-catenin. Conclusion: LL-37 may be a critical molecular link between tumor-supportive immune cells and tumors, facilitating the progression of lung cancer.

Melatonin alleviates aluminium toxicity through modulating antioxidative enzymes and enhancing organic acid anion exudation in soybean.

Aluminium (Al) toxicity is a major chemical constraint limiting plant growth and production on acidic soils. Melatonin (N-acetyl-5-methoxytryptamine) is a ubiquitous molecule that plays crucial roles in plant growth and stress tolerance. However, there is no knowledge regarding whether melatonin is involved in plant responses to Al stress. Here, we show that optimal concentrations of melatonin could effectively ameliorate Al-induced phytotoxicity in soybean (Glycine max L.). The concentration of melatonin in roots was significantly increased by the 50µM Al treatment. Such an increase in endogenous melatonin coincided with the upregulation of the gene encoding acetyltransferase NSI-like (nuclear shuttle protein-interacting) in soybean roots. Supplementation with low concentrations of melatonin (0.1 and 1µM) conferred Al resistance as evident in partial alleviation of root growth inhibition and decreased H2O2 production: in contrast, high concentrations of melatonin (100 and 200µM) had an opposite effect and even decreased root growth in Al-exposed seedlings. Mitigation of Al stress by the 1µM melatonin root treatment was associated with enhanced activities of the antioxidant enzymes and increased exudation of malate and citrate. In conclusion, melatonin might play a critical role in soybean resistance to Al toxicity.

Role of the plasma membrane H(+)-ATPase in the regulation of organic acid exudation under aluminum toxicity and phosphorus deficiency.

Aluminum (Al) toxicity and phosphorus (P) deficiency are 2 major limiting factors for plant growth and crop production in acidic soils. Organic acids exuded from roots have been generally regarded as a major resistance mechanism to Al toxicity and P deficiency. The exudation of organic acids is mediated by membrane-localized OA transporters, such as ALMT (Al-activated malate transporter) and MATE (multidrug and toxic compound extrusion). Beside on up-regulation expression of organic acids transporter gene, transcriptional, translational and post-translational regulation of the plasma membrane H(+)-ATPase are also involved in organic acid release process under Al toxicity and P deficiency. This mini-review summarizes the current knowledge about this field of study on the role of the plasma membrane H(+)-ATPase in organic acid exudation under Al toxicity and P deficiency conditions.