Effects Of Multiple Types Research Articles

The potential of diallyl trisulfide for cancer prevention and treatment, with mechanism insights.

Cancer has become an important public health problem worldwide, and there is currently a lack of effective treatment and prevention strategies. Natural plant active ingredients have been proven to be a safe and highly promising method for preventing and treating cancer. It has been found that diallyl trisulfide have anticancer effects in multiple types of cancer via inhibiting cancer proliferation, enhancing chemotherapy sensitivity, inducing apoptosis/autophagy, suppressing invasion/migration, regulating microenvironment. With the deepening of research on new strategies for cancer prevention and treatment, the role of diallyl trisulfides in cancers occurrence, prognosis, and drug resistance is also receiving increasing attention. In order to better understand the relationship between diallyl trisulfides and various cancer, as well as the role and mechanism of diallyl trisulfides in cancer prevention and treatment, we briefly summarized the role and function of diallyl trisulfide in cancers.

Anlotinib destabilizes PAX3-FOXO1 to induce rhabdomyosarcoma cell death via upregulating NEK2

BackgroundRhabdomyosarcoma (RMS) is one of the most common soft tissue sarcomas in children and adolescents, in which PAX3-FOXO1 fusion gene positive patients have very poor prognosis. PAX3-FOXO1 has been identified as an independent prognostic predictor in RMS, with no currently available targeted therapeutic intervention. The novel tyrosine kinase inhibitor anlotinib exhibits a wide range of anticancer effects in multiple types of cancers; however, there have been no relevant studies regarding its application in RMS. Materials and methodsWe investigated the effects of PAX3-FOXO1 on the therapeutic efficacy of anlotinib using the CCK-8 assay, flow cytometry, invasion assay, wound healing assay, western blotting, quantitative polymerase chain reaction(qPCR), and xenograft experiments. RNA-seq and co-immunoprecipitation assays were conducted to determine the specific mechanism by which anlotinib regulates PAX3-FOXO1 expression. ResultsAnlotinib effectively inhibited RMS cell proliferation and promoted apoptosis and G2/M phase arrest while impeding tumor growth in vivo. Downregulation of PAX3-FOXO1 enhances the antitumor effects of anlotinib. Anlotinib upregulates protein kinase NEK2 and increases the degradation of PAX3-FOXO1 via the ubiquitin-proteasome pathway, leading to a reduction in PAX3-FOXO1 protein levels. ConclusionAnlotinib effectively inhibited the malignant progression of RMS and promoted degradation of the fusion protein PAX3-FOXO1. Anlotinib could be a targeted therapeutic approach to treat PAX3-FOXO1 fusion-positive RMS.

The Spop/BRD4/c-Myc Axis Modulates IMiDs Sensitivity in Multiple Myeloma

The development of novel agents including immunomodulatory drugs (IMiDs) lenalidomide (Len) and pomalidomide (Pom) has led to improved patient outcomes in multiple myeloma (MM); however, MM patients inevitably experience relapse and drug resistance. The expression level of CRBN, CRBN-binding proteins, and CRL4 CRBN ubiquitin ligase is considered to be associated with IMiDs resistance. Clinical studies have shown that MM patients can exhibit IMiDs resistance even without CRBN abnormalities, suggesting the molecular mechanisms of intrinsic resistance to IMiDs are not fully understood. To delineate the molecular mechanisms underlying IMiDs resistance, we performed genome-wide knockout (KO) screening in IMiDs-sensitive MM cells. For in vitro work, we used the MM cell lines MM1S, and H929. We used sgRNA to KO SPOP and BRD4 in MM cells. After performing a CRISPR KO screen in MM cells, we discovered that in addition to CRBN and its associated genes, sgRNAs targeting SPOP (speckle-type POZ protein, a speckled zinc finger protein) were highly enriched after treatment with Poma. Importantly, SPOP KO MM cell lines acquired significant resistance to Pom and Len treatment. To examine whether SPOP KO-induced IMiDs resistance was CRBN-pathway dependent, we assessed CRBN and its downstream interacting protein levels. SPOP KO showed no effect on CRBN expression; moreover, IMiDs can still trigger IKZF1 and IKZF3 degradation, associated with the downregulation of IRF4, suggesting that SPOP mediates sensitivity to IMiDs in a mechanism independent of CRBN-IKZF1/3 axis.Compared to plasma cells from normal donors, we found that the expression levels of SPOP were significantly decreased in MGUS patients, smoldering myeloma patients, newly diagnosed MM patients, and refractory relapsed MM patients (p-values: 2.4e-2, 2.0e-4, 9.9e-3, 3.17e-6, respectively). SPOP is the adaptor protein of the Cullin3-RING ubiquitin ligase complex. Therefore, the function of SPOP is determined by the characteristics of the substrates it recruits. We performed immunoprecipitation with overexpressed SPOP in MM cells, followed by mass spectrometry analysis, and identified BRD4 as a candidate protein binding to SPOP in MM, which was confirmed by Co-IP. KO of SPOP led to an upregulation of BRD4 protein levels in MM cells. As a downstream regulator of BRD4, the oncogene c-Myc showed a significant increase in protein expression in IMiDs-resistant MM patients. Furthermore, the KO of SPOP notably enhanced c-Myc expression in MM cells, while the KO of BRD4 in SPOP KO MM cells decreaed c-Myc expression and restored MM cell sensitivity to IMiD treatment. These findings suggest that SPOP modulates c-Myc expression through BRD4 in a CRBN-IKZF1/3 independent manner, thereby mediating MM cell sensitivity to IMiDs. BRD4 plays a significant role in the development and progression of various tumors. The BRD4 inhibitor JQ1 has been shown to exhibit anti-tumor effects in multiple types of cancer. We found that combination treatment with JQ-1 and IMiDs reversed IMiDs resistance of SPOP KO MM cell lines and primary MM cells from relapsed patients. Our data show that SPOP is a CRBN-independent modulator of IMiDs sensitivity by regulating the BRD4/c-Myc axis and provides the preclinical rationale for combining IMiDs with BRD4 inhibitors to overcome IMiDs resistance and improve patient outcomes.

Electro-responsive micelle-based universal drug delivery system for on-demand therapy in epilepsy

A universal drug delivery system (DDS) with brain-targeted ability is demanded to enhance antiepileptic therapeutic efficacy and reduce side effects in multiple types of epileptic seizures. In this study, we reported a micelle-based DDS possessing the brain-targeted ability and electro-responsive feature for universal delivery of antiepileptic drugs (AEDs). The system is fabricated by ferrocene (Fc)-conjugated D-a-tocopherol polyethylene glycol succinate and amphiphilic block copolymer, which improve the drug encapsulation of different AEDs. Interestingly, the intrinsic nature of TPGS-Fc including transferrin receptor-mediated transcytosis and efflux pump inhibition endows the system with high permeability across the blood-brain barrier. Based on the hydrophobic-hydrophilic transition of Fc, the micelles can respond to epileptiform discharges and thus release the loaded AEDs. Improved antiepileptic efficacy of the micelles has been demonstrated in acute, continuous, and chronic epilepsy models. In summary, we have developed a universal micelle-based DDS for various AEDs delivery, which provides a promising approach to on-demand therapy of different epileptic seizures.

Abstract 4062: The discovery and development of a CRISPR/Cas9-engineered tumor-infiltrating lymphocytes product (GT316) as a next-generation TIL therapy

Abstract Adoptive cell therapy by tumor-infiltrating lymphocytes (TILs) has demonstrated promising therapeutic effects in multiple types of solid tumors and significantly prolonged the survival of late-stage patients. However, the “prone-to-exhaustion” phenotype of the final TIL product after rapid expansion during manufacture and the presence of various immunosuppressive mechanisms in tumor microenvironment (TME) compromises the persistence and anti-tumor efficacy of TIL post infusion. To discover potential immunoregulatory targets that could maximize the function of TIL, we established a genome-wide CRISPR/Cas9 screening platform, ImmuT Finder®, to unbiasedly identify functional gene targets in primary T cells. Notably, this platform employed T cells bearing a tumor-antigen specific TCR-T that were repeatedly stimulated by tumor cells with cognate tumor antigen and demonstrated similar exhaustion profile as TIL. We selected top 30 targets after several rounds of screening and quickly validated their function in a 96-well array. Then, the top targets that showed significantly enhancement in proliferation and function of TCR-T were further selected, and their combinational effects on TIL were tested both in vitro and in vivo. Finally, double KO of GT304 and GT312 (GT316) stands out as the most potent combination, which significantly improves TIL proliferation and cytokine release, eradicates tumor growth in both CDX and PDX mouse models and promotes long-term in vivo persistence with low-dependence on IL-2. Specific and potent sgRNAs targeting both targets have been selected, and manufacturing process of GT316 TIL product has been developed (KOReTIL®). In summary, these data demonstrated that our ImmuT Finder® platform enables unbiased discovery of potent and novel targets for the development of T cell therapy and support the clinical assessment of GT316 as a next-generation TIL therapy. Currently, an investigator-initiated trial of GT316 is ongoing in China. Citation Format: Yarong Liu, Jingwei Sun, Yao Sheng, Jingman Wang, Jiahui Jin, Fei Li, Lingyun Chen, Di Zhou, Yongchao Tan, Quanwei Wang, Zhao Xu, Haibao Li, Pin Wang, Jun Cui. The discovery and development of a CRISPR/Cas9-engineered tumor-infiltrating lymphocytes product (GT316) as a next-generation TIL therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4062.

TRIM58 Interacts with ZEB1 to Suppress NSCLC Tumor Malignancy by Promoting ZEB1 Protein Degradation via UPP.

Currently, how to successfully control refractory and metastatic diseases remains a fundamental goal for clinicians to improve therapeutic effects for patients with non-small cell lung cancer (NSCLC). Several studies have discovered that TRIM58, a member of tripartite motif protein family, shows antitumor effect in multiple types of cancer. In this study, we aimed to further clarify the molecular regulatory network of TRIM58 and corresponding targets for NSCLC patients. TRIM58 expression in clinical tumor tissue samples and cancer cell lines was examined. Functional experiments including cellular invasion, cell metastasis, chemoresistance assay, and ubiquitination evaluation experiments were conducted to investigate the interaction between TRIM58 and ZEB1, which is a prime element of transcription factor network that controls epithelial-to-mesenchymal transition. TRIM58 expression was characteristically decreased in NSCLC tumor tissues and cancer cell lines. Functional experiments demonstrated that TRIM58 suppression enhanced malignant biological behaviors including cellular survivability, migration, and invasion, as well as stem-like cellular phenotype of tumor cells. TRIM58 silencing also significantly enhanced the chemoresistance of NSCLC cells to chemoagents. TRIM58-ZEB1 interaction accelerated degradation of ZEB1 protein, thus further leading to the augment of tumor behaviors. Further detailed molecular experiments revealed that the interaction between TRIM58 and ZEB1 was mediated via ubiquitin-proteasome pathway (UPP). TRIM58 suppressed NSCLC through interacting with ZEB1 and promoting ZEB1 protein degradation via UPP. The present research sheds light on the interaction between TRIM58 and ZEB1, and TRIM58/ZEB1 axis might be the potential therapeutic targets of NSCLC.

Cannabidiol Interacts Antagonistically with Cisplatin and Additively with Mitoxantrone in Various Melanoma Cell Lines-An Isobolographic Analysis.

The medical application of cannabidiol (CBD) has been gathering increasing attention in recent years. This non-psychotropic cannabis-derived compound possesses antiepileptic, antipsychotic, anti-inflammatory and anxiolytic properties. Recent studies report that it also exerts antineoplastic effects in multiple types of cancers, including melanoma. In this in vitro study we tried to reveal the anticancer properties of CBD in malignant melanoma cell lines (SK-MEL 28, A375, FM55P and FM55M2) administered alone, as well as in combination with mitoxantrone (MTX) or cisplatin (CDDP). The effects of CBD on the viability of melanoma cells were measured by the MTT assay; cytotoxicity was determined in the LDH test and proliferation in the BrdU test. Moreover, the safety of CBD was tested in human keratinocytes (HaCaT) in LDH and MTT tests. Results indicate that CBD reduces the viability and proliferation of melanoma-malignant cells and exerts additive interactions with MTX. Unfortunately, CBD produced antagonistic interaction when combined with CDDP. CBD does not cause significant cytotoxicity in HaCaT cell line. In conclusion, CBD may be considered as a part of melanoma multi-drug therapy when combined with MTX. A special attention should be paid to the combination of CBD with CDDP due to the antagonistic interaction observed in the studied malignant melanoma cell lines.

Effects of harassment on psychological inflexibility/experiential avoidance among Taiwanese emergent adult gay and bisexual men

Gay and bisexual men are at a higher risk of mental and physical health problems than heterosexual men, reporting higher frequencies of harassment and discrimination in both housing and employment domains. Psychological inflexibility/experiential avoidance (PI/EA) refers to behaviors that are rigidly guided by psychological reactions rather than direct contingencies or personal values; PI/EA referring to a key psychopathology behavior related to greater mental illness. The objective of the study was to examine the association of various types of harassment with PI/EA and the effects of multiple types and site harassment on PI/EA among Taiwanese emergent adult gay and bisexual men. A total of 305 gay and bisexual men aged between 20 and 25 years were recruited into this study. The level of PI/EA and types of harassment were evaluated and further analysis the effect of harassment on PI/EA. Findings indicated that various types of harassment exerted significant effects on PI/EA in emergent adult gay and bisexual men; furthermore, the effect was cumulative. The result also revealed that victims of verbal ridicule and relational exclusion, victims of physical aggression and theft of belongings, and victims of cyber harassment had significantly higher PI/EA. Harassment experiences appeared to be significantly associated with PI/EA, and the effects could be cumulative. It would be beneficial to construct a friendly world for emergent adult gay and bisexual men. Evaluation and intervention with PI/EA improvement should be considered for emergent adult gay and bisexual men with traditional and cyber harassment experiences.

An Ensemble Denoiser Based on Generative Adversarial Networks to Eliminate Adversarial Perturbations

Deep neural networks (DNNs) have been applied in various machine learning tasks with the success of deep learning technologies. However, they are surprisingly vulnerable to adversarial examples, which can easily fool deep neural networks. Due to this drawback of deep neural networks, numerous methods have been proposed to eliminate the effect of adversarial examples. Although they do play a significant role in protecting deep neural networks, most of them all have one flaw in common. They are only effective for certain types of adversarial examples. This paper proposes an ensemble denoiser based on generative adversarial networks (GANs) to protect deep neural networks. This proposed method aims to remove the effect of multiple types of adversarial examples before they are fed into deep neural networks. Therefore, it is model-independent and cannot modify deep neural networks’ parameters. We employ a generative adversarial network for this proposed method to learn multiple mappings between adversarial examples and benign examples. Each mapping behaves differently for different types of adversarial examples. Therefore, we integrate these mappings as the ultimate method to defend against multiple types of adversarial examples. Experiments are conducted on the MNIST and CIFAR10 datasets. We compare this proposed method with several existing excellent methods. Results show that this proposed method achieves better performance than other methods when defending against multiple types of adversarial examples. The code is available at <a href="https://github.com/Afreadyang/ensemble-ape-gan">https://github.com/Afreadyang/ensemble-ape-gan</a>

Osthole Inhibits Breast Cancer Progression through Upregulating Tumor Suppressor GNG7.

Osthole (OST) is a plant-derived compound that can inhibit the proliferation of tumor cells and has a tumor-suppressive effect in multiple types of cancers. However, the mechanisms of OST-mediated breast cancer (BrCa) inhibition were still largely unknown. In this study, we made full use of the GSE85871 dataset to identify potential targets of OST in BrCa via multiple bioinformatics analysis. Next, a series of in vitro experiments were conducted to check the role of GNG7 in BrCa and the relationship between OST and GNG7. Through a series of bioinformatics analyses, GNG7 was identified as a potential target of OST, which could be significant upregulated by OST exposure in BrCa cells. Besides, GNG7 was lowly expressed in BrCa tissues compared with normal breast tissues, and BrCa patients with low GNG7 expression had shorter overall survival (OS) and relapse-free survival (RFS) compared with those with high GNG7 expression. Moreover, GNG7 silencing significantly enhanced cell proliferation and inhibited apoptosis, and exogenous overexpression of GNG7 showed reverse effects on BrCa cells. Last but not least, GNG7 inhibition could notably rescue OST-mediated cytotoxic effects. In summary, we identified GNG7 as a novel target for OST in BrCa and a potential tumor suppressor. Thus, OST could be therapeutically beneficial for BrCa through a GNG7-dependent mechanism.

Relationships Among Types of Activity Engagement and Sleep Quality Among Older Adults

There is increasing awareness that lack of activity engagement is associated with poor sleep quality. However, the majority of studies have focused on the effect of a single type of activity engagement on sleep quality. Little is known about the combined effect of multiple types of activity engagement on sleep quality. The aim of this study is to identify relationships among different types of activity engagement and sleep quality among older adults. This study is a secondary data analysis using the Health and Retirement Study data. The participants included 3,357 persons who were age 65 or older and who responded to survey modules on activity engagement and sleep quality in 2016. Before we conducted primary analysis, factor analyses and calculating coefficient omega were conducted to identify factor structure, construct validity and reliability of the activity engagement questionnaire. Then, regression was conducted to examine the relationships among multiple types of activity engagement and sleep quality after adjusting for covariates based on the senescent sleep model. Exploratory and confirmatory factor analysis showed the 14-item questionnaire was comprised of three factors; social, cognitive, and physical activity and the three-factor model showed adequate validity and reliability. In the regression model social (β=0.25, p=0.033) and cognitive (β=0.36, p=0.001) activity engagement were positively related to better sleep quality. Based on these results, future research is needed to identify the mechanisms in which social and cognitive activities influence sleep quality positively and to develop targeted activity interventions for older adults.

Cantharidin Induces Apoptosis and Promotes Differentiation of AML Cells Through Nuclear Receptor Nur77-Mediated Signaling Pathway.

BackgroundAcute myeloid leukemia (AML) is a hematopoietic malignancy characterized by uncontrolled proliferation and accumulation of myeloblasts in the bone marrow (BM), blood, and other organs. The nuclear receptors Nur77 is a common feature in leukemic blasts and has emerged as a key therapeutic target for AML. Cantharidin (CTD), a main medicinal component of Mylabris (blister beetle), exerts an anticancer effect in multiple types of cancer cells.PurposeThis study aims to characterize the anti-AML activity of CTD in vitro and in vivo and explore the potential role of Nur77 signaling pathway.Study Design/MethodsThe inhibition of CTD on cell viability was performed in different AML cells, and then the inhibition of CTD on proliferation and colony formation was detected in HL-60 cells. Induction of apoptosis and promotion of differentiation by CTD were further determined. Then, the potential role of Nur77 signaling pathway was assessed. Finally, anti-AML activity was evaluated in NOD/SCID mice.ResultsIn our study, CTD exhibited potent inhibition on cell viability and colony formation ability of AML cells. Moreover, CTD significantly induced the apoptosis, which was partially reversed by Z-VAD-FMK. Meanwhile, CTD promoted the cleavage of caspases 8, 3 and PARP in HL-60 cells. Furthermore, CTD obviously suppressed the proliferation and induced the cell cycle arrest of HL-60 cells at G2/M phase. Meanwhile, CTD effectively promoted the differentiation of HL-60 cells. Notably, CTD transiently induced the expression of Nur77 protein. Interestingly, CTD promoted Nur77 translocation from the nucleus to the mitochondria and enhanced the interaction between Nur77 and Bcl-2, resulting in the exposure of the BH3 domain of Bcl-2, which is critical for the conversion of Bcl-2 from an antiapoptotic to a proapoptotic protein. Importantly, silencing of Nur77 attenuated CTD-induced apoptosis, reversed CTD-mediated cell cycle arrest and differentiation of HL-60 cells. Additionally, CTD also exhibited an antileukemic effect in NOD/SCID mice with the injection of HL-60 cells into the tail vein.ConclusionsOur studies suggest that Nur77-mediated signaling pathway may play a critical role in the induction of apoptosis and promotion of differentiation by CTD on AML cells.

Intimate Partner Violence Victimization and Depressive Symptoms in Sichuan, China: Are There Gender Variations?

An emerging body of research has linked intimate partner violence (IPV) victimization with negative mental health outcomes among women in postreform China. However, limited scholarly attention has been given to the independent effects of multiple types of IPV victimization on depressive symptoms among men and women. Little is known if these independent effects will vary by gender in China where research on the association between IPV victimization and mental health did not emerge until fairly recently. Given this research paucity, this study aims to (a) examine the independent effects of different types of lifetime IPV victimization among married men and women in Sichuan province on their self-reported past 30-day depressive symptoms and (b) explore possible gender variations in these effects. The data utilized in this study came from a subsample of married men (N = 1,083) and women (N = 1,185) from the Third Survey of Chinese Women's Social Status 2010, a representative sample of adults aged 18 to 64 in Sichuan province. Statistical analyses indicate that all types of lifetime IPV victimization are significantly and positively associated with past 30-day depressive symptoms for women, whereas for men lifetime experiences of general controlling behavior and sexual IPV were not statistically associated with depressive symptoms. Moreover, the effects of multiple types of IPV victimization on depressive symptoms do not significantly vary by gender. Bearing this gender-neutral pattern in mind, health professionals, governmental officials, and researchers are strongly encouraged to focus on both married men and women in their IPV and mental health intervention, prevention, and treatment endeavors in postreform China.

Matrine inhibits cell growth, migration, invasion and promotes autophagy in hepatocellular carcinoma by regulation of circ_0027345/miR-345-5p/HOXD3 axis

BackgroundMatrine has been reported to exert anti-tumor effects in multiple types of cancers containing hepatocellular carcinoma (HCC). However, the anti-tumor molecular mechanisms of matrine in HCC is still not fully revealed.MethodsCell viability, apoptosis, cycle, migration and invasion were determined by Cell counting kit-8 (CCK-8), Flow cytometry and Transwell assays, respectively. Levels of all protein were analyzed by western blot analysis. The levels of circular RNA_0027345 (circ_0027345), microRNA-345-5p (miR-345-5p) and homeobox-containingD3 (HOXD3) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The interaction between circ_0027345 and circ_0027345 was identified using dual-luciferase reporter assay. The mouse xenograft model was constructed to explore the effect of matrine on tumor growth in vivo.ResultsMatrine suppressed cell growth, migration and invasion, while promoted apoptosis and autophagy in HCC cells. Matrine down-regulated the levels of circ_0027345 and HOXD3, and up-regulated miR-345-5p expression. Besides, circ_0027345 overexpression could reverse the inhibitory effect of matrine on cell progression. As the target gene of circ_0027345, miR-345-5p elevation counteracted the promotion effect of circ_0027345 overexpression on development of HCC cells. Moreover, miR-345-5p knockdown could facilitate cell growth, migration, invasion and repress cell apoptosis and autophagy by targeting HOXD3. Meanwhile, matrine restrained tumor growth of HCC by regulating circ_0027345/miR-345-5p/HOXD3 axis in vivo.ConclusionMatrine inhibited cell development and tumorigenesis in HCC by increasing miR-345-5p and decreasing circ_0027345 and HOXD3.

Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion

Fat mass and obesity-associated protein (FTO), an RNA N6-methyladenosine (m6A) demethylase, plays oncogenic roles in various cancers, presenting an opportunity for the development of effective targeted therapeutics. Here, we report two potent small-molecule FTO inhibitors that exhibit strong anti-tumor effects in multiple types of cancers. We show that genetic depletion and pharmacological inhibition of FTO dramatically attenuate leukemia stem/initiating cell self-renewal and reprogram immune response by suppressing expression of immune checkpoint genes, especially LILRB4. FTO inhibition sensitizes leukemia cells to Tcell cytotoxicity and overcomes hypomethylating agent-induced immune evasion. Our study demonstrates that FTO plays critical roles in cancer stem cell self-renewal and immune evasion and highlights the broad potential of targeting FTO for cancer therapy.

Cell Differentiation Agent-2 (CDA-2) Inhibits the Growth and Migration of Saos-2 Cells via miR-124/MAPK1.

BackgroundCDA-2 (cell differentiation agent 2), isolated from healthy human urine, exerts antitumor effects in multiple types of cancer cells. However, its role in osteosarcoma has not been studied.MethodsThe MTT assay was used to examine the cell proliferation rate. A colony formation assay was used to examine cell growth. The Transwell assay was used to examine cell migration ability. A real-time PCR assay was used to examine the expression levels of miR-124 and MAPK1. A Western blot assay was used to examine protein expression levels. MAPK1 was selected as a possible target of miR-124, and the targeting relationship was examined by a luciferase reporter assay.ResultsWe revealed that CDA-2 decreased the growth, migration and invasion ability of the osteosarcoma cell line Saos-2. Further study revealed that CDA-2 elevated the expression level of miR-124. MAPK1 was identified as a downstream target of miR-124. Knockdown of miR-124 or overexpression of MAPK1 counteracted CDA-2’s effects on cell growth and invasion.ConclusionOur data revealed that the miR-124/MAPK1 axis mediated CDA-2’s function in Saos-2 cells. CDA-2 can be used as a new treatment strategy for osteosarcoma.

PITPNC1 fuels radioresistance of rectal cancer by inhibiting reactive oxygen species production.

Neoadjuvant radiotherapy is a commonly used method for the current standard-of-care for most patients with rectal cancer, when the effects of radioresistance are limited. The phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1), a lipid-metabolism-related gene, has previously been proved to manifest pro-cancer effects in multiple types of cancer. However, whether PITPNC1 plays a role for developing radioresistance in rectal cancer patients is still unknown. Therefore, this study aims to investigate the role of PITPNC1 in rectal cancer radioresistance. Patient-derived tissue were used to detect the difference in the expression level of PITPNC1 between radioresistant and radiosensitive patients. Bioinformatic analyses of high-throughput gene expression data were applied to uncover the correlations between PITPNC1 level and oxidative stress. Two rectal cancer cell lines, SW620, and HCT116, were selected in vitro to investigate the effect of PITPNC1 on radioresistance, reactive oxygen species (ROS) generation, apoptosis, and proliferation in rectal cancer. PITPNC1 is highly expressed in radioresistant patient-derived rectal cancer tissues compared to radiosensitive tissue; therefore, PITPNC1 inhibits the generation of ROS and improves the extent of radioresistance of rectal cancer cell lines and then inhibits apoptosis. Knocking down PITPNC1 facilitates the production of ROS while application of the ROS scavenger, N-acetyl-L-cysteine (NAC), could reverse this effect. PITPNC1 fuels radioresistance of rectal cancer via the inhibition of ROS generation.

Cantharidin suppresses gastric cancer cell migration/invasion by inhibiting the PI3K/Akt signaling pathway via CCAT1

Cantharidin (CTD) is a traditional Chinese medicine that shows an anticancer effects in multiple types of cancer cells. However, the mechanism of CTD anti-cancer function in gastric cancer (GC) is still unclear. The aim of the present study was to investigate the underlying mechanism that CTD inhibits proliferation and migration through suppression of the PI3K/Akt signaling. CTD induced GC cell apoptosis and inhibited metastasis measured by CCK8 assays as well as wound healing assays and transwell assays. Mechanistic investigations suggested that CTD modulated the PI3K/Akt signaling via western-blot and quantitative q-PCR. In addition, we identified and confirmed CCAT1 as a novel direct target of CTD inhibited PI3K/AKt signaling expression. In conclusion, our results provide new point into the critical role of CTD in suppressing PI3K/Akt signaling via down-regulation of CCAT1, resulting in suppression GC cell growth and migration/invasion.

Immune cells within the tumor microenvironment: Biological functions and roles in cancer immunotherapy.

The immune cells within the tumor microenvironment (TME) play important roles in tumorigenesis. It has been known that these tumor associated immune cells may possess tumor-antagonizing or tumor-promoting functions. Although the tumor-antagonizing immune cells within TME tend to target and kill the cancer cells in the early stage of tumorigenesis, the cancer cells seems to eventually escape from immune surveillance and even inhibit the cytotoxic function of tumor-antagonizing immune cells through a variety of mechanisms. The immune evasion capability, as a new hallmark of cancer, accidently provides opportunities for new strategies of cancer therapy, namely harnessing the immune cells to battle the cancer cells. Recently, the administrations of immune checkpoint modulators (represented by anti-CTLA4 and anti-PD antibodies) and adoptive immune cells (represented by CAR-T) have exhibited unexpected antitumor effect in multiple types of cancer, bringing a new era for cancer therapy. Here, we review the biological functions of immune cells within TME and their roles in cancer immunotherapy, and discuss the perspectives of the basic studies for improving the effectiveness of the clinical use.

Immune checkpoint modulators in cancer immunotherapy: Recent advances and combination rationales.

As a new hallmark of cancer, immune surveillance evading plays a critical role in carcinogenesis. Through modulating the immune checkpoints, immune cells in tumor microenvironment can be harnessed to battle cancer cells. In recent years, the administration of anti-CTLA or/and anti-PD-1/L1 antibody has exhibited unexpected antitumor effect in multiple types of cancer, motivating the researchers to find more potential immune checkpoints as clinical targets. A wealth of clinical trials have been done to evaluate the safety and efficacy of monotherapy or combination therapy with immune checkpoint modulators. However, there still exist problems such as low response rate and adverse events in the clinical, which in turn leads us to the basic study. The better understanding of the crosstalk between the immune cells and the cancer cells within the microenvironment may inspire us new ideas for cancer treatment. In this review, we mainly summarize the recent advances in application of immune checkpoint modulators and the combination rationales, and discuss the problems existing in the precision therapy with immune checkpoint modulators.