Beyond a tumor suppressor: Soluble E-cadherin promotes the progression of cancer.

E-cadherin (E-cad) plays important roles in tumorigenesis as well as in tumor progression, invasion and metastasis. This protein exists in two forms: a membrane-tethered form and a soluble form. Full-length E-cad is membrane tethered. As a type I transmembrane glycoprotein, E-cad mainly mediates adherens junctions between cells and is involved in maintaining the normal structure of epithelial tissues. Soluble E-cad (sE-cad) is the extracellular fragment of the protein that is cleaved from the membrane after proteolysis of full-length E-cad. The production of sE-cad undermines adherens junctions, causing a reduction in cell aggregation capacity; furthermore, sE-cad can diffuse into the extracellular environment and the blood. As a paracrine/autocrine signaling molecule, sE-cad activates or inhibits multiple signaling pathways and participates in the progression of various types of cancer, such as breast cancer, ovarian cancer, and lung cancer, by promoting invasion and metastasis. This article briefly reviews the role of sE-cad in tumorigenesis and tumor progression and its significance in clinical therapeutics.

An aldehyde dehydrogenase 1A3 inhibitor attenuates the metastasis of human colorectal cancer.

Metastasis is the leading cause of death for patients with colorectal cancer (CRC). The development of therapeutic regimens that selectively inhibit the biological processes involved in CRC cell dissemination is important. We used multiple Affymetrix DNA microarray hybridization datasets to identify genes related to metastasis and have significant prognostic value for patients with CRC. Quantitative real-time PCR, immunofluorescent and immunohistochemical staining were used to evaluate mRNA and protein expression. The function of aldehyde dehydrogenase 1A3 (ALDH1A3) in invasion was assessed by performing transwell assays and animal experiments. Real-time PCR, luciferase reporter assays, and western blotting were used to identify the genes regulated by ALDH1A3. Molecular docking, MTS assays, cellular thermal shift assays, isothermal titration calorimetry, microscale thermophoresis, and enzymatic activity assays were used to screen and verify the efficacy of the ALDH1A3-specific inhibitor YD1701 (dibenzo-30-crown10-ether). Finally, subcutaneous or orthotopic xenograft models were established to investigate the therapeutic potential of YD1701. Human ALDH1A3 was identified to correlate with a metastatic phenotype in CRC cells and a poor patient prognosis. Moreover, ALDH1A3 upregulated the expression of ZEB1 and SNAI2 by inhibiting miR-200 family members. The ALDH1A3-specific inhibitor YD1701 was screened, attenuated the invasion of CRC cells in vitro, and prolonged the survival of mice bearing subcutaneous or orthotopic xenografts. Our results show that ALDH1A3 promotes invasion and metastasis via the miR-200-ZEB1/SANI2 axis and is thus a plausible marker for predicting CRC progression. Inhibiting ALDH1A3 with the identified compound YD1701 might represent an effective therapeutic approach to prevent the metastasis of CRC.

High-fat diet impairs ferroptosis and promotes cancer invasiveness via downregulating tumor suppressor ACSL4 in lung adenocarcinoma.

BACKGROUND: Long-chain acyl-CoA synthetase-4 (ACSL4) is involved in fatty acid metabolism, and aberrant ACSL4 expression could be either tumorigenic or tumor-suppressive in different tumor types. However, the function and clinical significance of ACSL4 in lung adenocarcinoma remain elusive. RESULTS: ACSL4 was frequently downregulated in lung adenocarcinoma when analyzing both the TCGA database and the validation samples, and the lower ACSL4 expression was correlated with a worse prognosis. Using gene set enrichment analysis, we found that high ACSL4 expression was frequently associated with the oxidative stress pathway, especially ferroptosis-related proteins. In vitro functional studies showed that knockdown of ACSL4 increased tumor survival/invasiveness and inhibited ferroptosis, while ACSL4 overexpression exhibited the opposite effects. Moreover, high-fat treatment could also inhibit erastin-induced ferroptosis by affecting ACSL4 expression. The anti-tumor effects of ferroptosis inducers and the anti-ferroptosis effects of the high-fat diet were further validated using the mouse xenograft model. CONCLUSIONS: ACSL4 plays a tumor-suppressive role in lung adenocarcinoma by suppressing tumor survival/invasiveness and promoting ferroptosis. Our study provided a theoretical reference for the application of ferroptotic inducers and dietary guidance for lung adenocarcinoma patients.

Kinome siRNA screen identifies SMG-1 as a negative regulator of hypoxia-inducible factor-1alpha in hypoxia.

Hypoxia-inducible factor-1 (HIF-1) plays a central role in tumor progression by regulating genes involved in proliferation, glycolysis, angiogenesis, and metastasis. To improve our understanding of HIF-1 regulation by kinome, we screened a kinase-specific small interference RNA library using a hypoxia-response element (HRE) luciferase reporter assay under hypoxic conditions. This screen determined that depletion of cellular SMG-1 kinase most significantly modified cellular HIF-1 activity in hypoxia. SMG-1 is the newest and least studied member of the phosphoinositide 3-kinase-related kinase family, which consists of ATM, ATR, DNA-PKcs, mTOR, and SMG-1. We individually depleted members of the phosphoinositide 3-kinase-related kinase family, and only SMG-1 deficiency significantly augmented HIF-1 activity in hypoxia. We subsequently discovered that SMG-1 kinase activity was activated by hypoxia, and depletion of SMG-1 up-regulated MAPK activity under low oxygen. Suppressing cellular MAPK by silencing ERK1/2 or by treatment with U0126, a MAPK inhibitor, partially blocked the escalation of HIF-1 activity resulting from SMG-1 deficiency in hypoxic cells. Increased expression of SMG-1 but not kinase-dead SMG-1 effectively inhibited the activity of HIF-1alpha. In addition, cellular SMG-1 deficiency increased secretion of the HIF-1alpha-regulated angiogenic factor, vascular epidermal growth factor, and survival factor, carbonic anhydrase IX (CA9), as well as promoted the hypoxic cell motility. Taken together, we discovered that SMG-1 negatively regulated HIF-1alpha activity in hypoxia, in part through blocking MAPK activation.

Pan-cancer analysis reveals synergistic effects of CDK4/6i and PARPi combination treatment in RB-proficient and RB-deficient breast cancer cells.

DNA damage results in mutations and plays critical roles in cancer development, progression, and treatment. Targeting DNA damage response in cancers by inhibiting poly-(ADP-ribose) polymerases (PARPs) offers an important therapeutic strategy. However, the failure of PARP inhibitors to markedly benefit patients suggests the necessity for developing new strategies to improve their efficacy. Here, we show that the expression of cyclin-dependent kinase 4/6 (CDK4/6) complex members significantly correlates with mutations (as proxies of DNA damages), and that the combination of CDK4/6 and PARP inhibitors shows synergy in both RB-proficient and RB-deficient breast cancer cells. As PARPs constitute sensors of DNA damage and are broadly involved in multiple DNA repair pathways, we hypothesized that the combined inhibition of PARPs and DNA repair (or repair-related) pathways critical for cancer (DRPCC) should show synergy. To identify druggable candidate DRPCC(s), we analyzed the correlation between the genome-wide expression of individual genes and the mutations for 27 different cancer types, assessing 7146 exomes and over 1,500,000 somatic mutations. Pathway enrichment analyses of the top-ranked genes correlated with mutations indicated "cell cycle pathway" as the top candidate DRPCC. Additionally, among functional cell-cycle complexes, the CDK4/6 complex showed the most significant negative correlation with mutations, also suggesting that combined CDK4/6 and PARP inhibition might exhibit synergy. Furthermore, combination treatment showed synergy in not only RB-proficient but also RB-deficient breast cancer cells in a reactive oxygen species-dependent manner. These findings suggest a potential therapeutic strategy to improve the efficacy of PARP and CDK4/6 inhibitors in cancer treatment.

Author Correction: Invasion of white matter tracts by glioma stem cells is regulated by a NOTCH1-SOX2 positive-feedback loop.

The original and corrected figures are shown in the accompanying Author Correction.

Invasion of white matter tracts by glioma stem cells is regulated by a NOTCH1-SOX2 positive-feedback loop.

Early invasive growth along specific anatomical structures, especially the white matter tract, is regarded as one of the main causes of poor therapeutic outcome of people with gliomas. We show that some glioma stem cells (GSCs) are preferentially located along white matter tracts, which exhibit a demyelinated phenotype, at the invasive frontier of glioma tissues. These GSCs are CD133+Notch1+, whereas the nerve fibers express the Notch ligand Jagged1. The Notch-induced transcription factor Sox9 promotes the transcription of SOX2 and the methylation level of the NOTCH1 promoter is attenuated by the upregulation of SOX2 to reinforce NOTCH1 expression in GSCs. This positive-feedback loop in a cohort of glioma subjects is correlated with a poor prognosis. Inhibition of Notch signaling attenuates the white-matter-tract tropism of GSCs. These findings provide evidence indicating that the NOTCH1-SOX2 positive-feedback loop controls GSC invasion along white matter tracts.

[Identification and genetic study of major genes of resistance to Cerospora Sojina Hara in soybean].

Soybean frogeye leaf spot is one of the main diseases in Heilongjiang province. Usually, under several physical races of Cerospora Sojina Hara existed condition, the inheritance of resistance to this disease is controlled by equal-effect polygene. While high resistant parent 'Dongnong 9674 and other sensitive parents were used to make the three resistance-sensitive combinations in this paper, the resistance to Cerospora Sojina Hara had appeared the significant major gene effect. When P1, P2, F1, F2, B1, and B2 six generations were used to study and estimate the gene effects, major genes of resistance to Cerospora Sojina Hara were identified and the genetic parameters were also estimated in three combinations. The inheritance of genes resistant to this disease was fitted to the major gene and polygene mixed inheritance model or two gene loci inheritance model. The estimation of genetic parameters indicated that the additive, dominance and epistasis effects were existed and played an important role in the resistance to Cerospora Sojina Hara. It is meaningful in soybean resistance breeding to frogeye leaf spot.

CDC25B mediates rapamycin-induced oncogenic responses in cancer cells.

Because the mammalian target of rapamycin (mTOR) pathway is commonly deregulated in human cancer, mTOR inhibitors, rapamycin and its derivatives, are being actively tested in cancer clinical trials. Clinical updates indicate that the anticancer effect of these drugs is limited, perhaps due to rapamycin-dependent induction of oncogenic cascades by an as yet unclear mechanism. As such, we investigated rapamycin-dependent phosphoproteomics and discovered that 250 phosphosites in 161 cellular proteins were sensitive to rapamycin. Among these, rapamycin regulated four kinases and four phosphatases. A siRNA-dependent screen of these proteins showed that AKT induction by rapamycin was attenuated by depleting cellular CDC25B phosphatase. Rapamycin induces the phosphorylation of CDC25B at Serine375, and mutating this site to Alanine substantially reduced CDC25B phosphatase activity. Additionally, expression of CDC25B (S375A) inhibited the AKT activation by rapamycin, indicating that phosphorylation of CDC25B is critical for CDC25B activity and its ability to transduce rapamycin-induced oncogenic AKT activity. Importantly, we also found that CDC25B depletion in various cancer cell lines enhanced the anticancer effect of rapamycin. Together, using rapamycin phosphoproteomics, we not only advance the global mechanistic understanding of the action of rapamycin but also show that CDC25B may serve as a drug target for improving mTOR-targeted cancer therapies.