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Drug resistance causes failure of cancer treatment. Identifying drug sensitivity of tumors can guide therapeutic administration for cancer patients, however this approach lacks a facile, fast, and noninvasive evaluation platform. Herein, a gelatin‐coated ZnO array nanoplatform to isolate circulating tumor cells (CTCs) is developed, and their drug resistance for inspecting tumor sensitivity is assessed. The nanoplatform is comprised of a nanosubstrate of ZnO submicropillars (ZnO SMPs) for efficiently isolating cancer cells, and Au nanoparticles (AuNPs) based electrochemical probes for evaluating drug resistance of the captured cells. Gelatin, an extracellular matrix‐like and enzyme‐degradable material, is used to coat ZnO SMPs and AuNPs, endowing the nanoplatform with the ability to maintain cancer cell viability and realize enzyme‐responsive cell recovery for downstream bioanalysis. This nanoplatform is expected to noninvasively evaluate drug sensitivity of cancer patients through simple liquid biopsy of CTCs in peripheral blood and benefit the treatment. [ABSTRACT FROM AUTHOR]

Purpose: Colorectal cancer (CRC) is one of the most common carcinomas worldwide with a high mortality rate. Numerous studies suggest that circular RNA (circRNA) plays a crucial role in the progression of various carcinomas, including CRC. The present work focused on exploring the role and underlying molecular mechanism of action of the circRNA circLRCH3 in CRC. Methods: Real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was conducted to detect expression levels of circLRCH3, miR-233, and lipoma preferred partner (LPP). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to measure the proliferation of CRC cells and the transwell assay was used to evaluate cell migration and invasion capacity. A flow cytometry assay was used to analyze the effect of circLRCH3 on the distribution of the cell cycle and apoptosis of CRC cells. The expression of LPP was analyzed using Western blotting or an RT-qPCR assay. The relationship between miR-223 and circLRCH3, and that between miR-223 and LPP, was predicted and examined using bioinformatics analysis and luciferase reporter gene experiments. A xenograft tumor formation assay was also performed. Results: We found that the expression level of circLRCH3 was downregulated in CRC cells and negatively correlated with miR-223. The overexpression of circLRCH3 or silencing of miR-223 inhibited the growth, invasion, and migration of CRC cells, but promoted their apoptosis. In contrast, overexpression of miR-223 and depletion of LPP severally abrogated the tumor suppressive roles of circLRCH3 and miR-223 knockdown in CRC cells in vitro. The xenograft experiments in nude mice also proved the antitumor effect of circLRCH3. Conclusion: These results suggested that the circLRCH3/miR-223/LPP axis likely plays a critical role in CRC. [ABSTRACT FROM AUTHOR]

NK2 homeobox 5 (Nkx2.5), a homeobox-containing transcription factor, is associated with a spectrum of congenital heart diseases. Recently, Nkx2.5 was also found to be differentially expressed in several kinds of tumors. In colorectal cancer (CRC) tissue and cells, hypermethylation of Nkx2.5 was observed. However, the roles of Nkx2.5 in CRC cells have not been fully elucidated. In the present study, we assessed the relationship between Nkx2.5 and CRC by analyzing the expression pattern of Nkx2.5 in CRC samples and the adjacent normal colonic mucosa (NCM) samples, as well as in CRC cell lines. We found higher expression of Nkx2.5 in CRC compared with NCM samples. CRC cell lines with poorer differentiation also had higher expression of Nkx2.5. Although this expression pattern makes Nkx2.5 seem like an oncogene, in vitro and in vivo tumor suppressive effects of Nkx2.5 were detected in HCT116 cells by establishing Nkx2.5-overexpressed CRC cells. However, Nkx2.5 overexpression was incapacitated in SW480 cells. To further assess the mechanism, different expression levels and mutational status of p53 were observed in HCT116 and SW480 cells. The expression of p21WAF1/CIP1, a downstream antitumor effector of p53, in CRC cells depends on both expression level and mutational status of p53. Overexpressed Nkx2.5 could elevate the expression of p21WAF1/CIP1 only in CRC cells with wild-type p53 (HCT116), rather than in CRC cells with mutated p53 (SW480). Mechanistically, Nkx2.5 could interact with p53 and increase the transcription of p21WAF1/CIP1 without affecting the expression of p53. In conclusion, our findings demonstrate that Nkx2.5 could act as a conditional tumor suppressor gene in CRC cells with respect to the mutational status of p53. The tumor suppressive effect of Nkx2.5 could be mediated by its role as a transcriptional coactivator in wild-type p53-mediated p21WAF1/CIP1 expression. [ABSTRACT FROM AUTHOR]

A disintegrin and metalloproteinase 8 (ADAM8) protein is a multi‐domain transmembrane glycoprotein which involves in extracellular matrix remodelling, cell adhesion, invasion and migration. ADAM8 and epithelial‐mesenchymal transition (EMT) play an important role in tumour invasion has been well established. However, the interaction between ADAM8 and EMT has remained unclear. The data of colon cancer patients obtained from TCGA (The Cancer Genome Atlas) and GTEx (Genotype‐Tissue Expression Project) were analysed by the bioinformatics research method. The expression of ADAM8 in colon cancer cells was up‐regulated and down‐regulated by transfecting with the expression plasmid and small interfering RNA, respectively. Transwell invasion assay, immunohistochemistry, immunocytochemistry, Western blotting and qRT‐PCR were utilized to study the effect of ADAM8 on colon cancer cell's EMT and its related mechanisms. Analysis of TCGA and GTEx data revealed that ADAM8 was linked to poor overall survival in colon cancer patients. Besides, ADAM8 was correlated with multiple EMT biomarkers (E‐cadherin, N‐cadherin, Vimentin, Snail2 and ZEB2). In vitro, we also proved that the up‐regulation of ADAM8 could promote EMT effect and enhance the invasive ability of colon cancer cells. On the contrary, the down‐regulation of ADAM8 in colon cancer cells attenuated these effects above. Further studies suggested that ADAM8 modulated EMT on colon cancer cells through TGF‐β/Smad2/3 signalling pathway. Our research suggested that ADAM8 could be a potential biomarker for the prognosis of colon cancer and induced EMT to promote the invasion of colon cancer cells via activating TGF‐β/Smad2/3 signalling pathway. [ABSTRACT FROM AUTHOR]

Anoikis (detachment‐induced cell death) is a specific type of programmed cell death which occurs in response to the loss of the correct extracellular matrix connections. Anoikis resistance is an important mechanism in cancer invasiveness and metastatic behavior. Autophagy, on the other hand, involves the degradation of damaged organelles and the recycling of misfolded proteins and intracellular components. However, the intersection of these two cellular responses in lung cancer cells has not been extensively studied. Here, we identified that upon matrix deprivation, the lymphocyte lineage‐specific Ets transcription factor SPIB was activated and directly enhanced SNAP47 transcription in certain lung cancer cells. Loss of attachment‐induced autophagy significantly increased anoikis resistance by SPIB activation. Consistent with this function, SPIB depletion by short hairpin RNA abrogated SNAP47 transcriptional activation upon matrix deprivation. Therefore, these data delineate an important role of SPIB in autophagy‐mediated anoikis resistance in lung cancer cells. Accordingly, these findings suggest that manipulating SPIB‐regulated pathways in vivo and evaluating the impact of anoikis resistance warrant further investigation. Database: RNA sequencing and ChIP sequencing data are available in Gene Expression Omnibus database under the accession numbers GSE106592 and GSE125561, respectively. [ABSTRACT FROM AUTHOR]

We report a new biofunctionalized nanoplatform based on hyaluronic acid-coated gold-nano-dot-decorated hollow carbon nanospheres (AuHCNs-HA) for microRNA imaging in living cells. Importantly, the HA-coated nanoplatform could be internalized into target cells via CD44 receptor-mediated endocytosis. It can be further applied for intracellular miR-21 imaging in CD44-positive colorectal cancer cells. [ABSTRACT FROM AUTHOR]

Cellular senescence, which can be defined as a stress response preventing the propagation of cells that have accumulated potentially oncogenic alterations, is invariably associated with a permanent cell cycle arrest. Enhancer of zeste homolog 2 (EZH2) as a member of polycomb group proteins and its targets include cell cycle regulatory proteins, which govern cell cycle progression and cellular senescence. In this study, we report that EZH2 depletion promotes the senescent state in human gastric cancer cells SGC-7901. We found that EZH2 functionally suppressed the senescent state in human gastric cancer cells SGC-7901. EZH2 depletion inhibited cell proliferation, arrested cellular cycle, restored features of a cellular senescence phenotype, and promoted doxorubicin-induced senescence. To prove that EZH2 expression contributes substantially to the change of key cell cycle regulators, we showed that p21 and p16 were activated to a certain extent upon EZH2 depletion and activation of p21 was in a p53-independent manner. Taken together, our data suggest that EZH2 depletion promotes the progression of senescence by mediating the activation of tumor suppressor genes p21 and p16, and could serve as a potential epigenetic target for gastric cancer therapy. [ABSTRACT FROM AUTHOR]

The role of CD4+ T helper (Th) 17 cells in malignancy is currently under debate. However, upon closer scrutiny, it becomes apparent that this discussion includes not only evaluations of Th17 cells but also IL-17+ cells from other immune populations, the cytokine interleukin (IL)-17 itself (both endogenous and exogenous) and IL-23. Further complicating the matter are occasionally conflicting results of studies in humans versus those in mice and contradictory data from immunocompetent versus immunodeficient mice. To better understand the role of Th17 cells in the tumor-bearing host, we focus first upon those studies investigating Th17 cells in patients and then those in mice, all the while keeping in mind that variables such as tumor-initiating agents, a pre-existing inflammatory environment and the immune competence of the host may have direct effects upon this T-cell subset. In this review, we will describe the phenotype of tumor-associated Th17 cells, review those studies that have examined the population directly, and finally, briefly discuss the studies involving Th17-associated signature cytokines. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate the effect of Rapamycin on epithelial-mesenchymal transition(EMT) of LoVo colonic adenocarcinoma cells in vitro. Methods: Cultured LoVo colonic adenocarcinoma cells were divided into three groups: negative control group, EMT-inducing group(TGF-β1) and EMT-interfering group(TGF-β1 plus Rapamycin). E-cadherin expression in LoVo cells was detected by Western Blot, while the expression of vimentin was evaluated through immunocytochemistry. The Snail mRNA in LoVo cells was examined by RT-PCR. Results: TGF-β1 induced LoVo cell switching from polygonal to spindle-shaped. TGF-β1 enhanced the expression of vimentin, but lowered the level of E-cadherin. In contrast, Rapamycin impaired the transition induced by TGF-β1. Rapamycin dramatically abrogated TGF-β1-induced vimentin expression and restored E-cadherin expression in LoVo cells. Rapamycin significantly repressed the up-regulation of Snail mRNA expression induced by TGF-β1. Conclusion: Rapamycin dramatically abrogated TGF-β1 induced Snail mRNA expression in LoVo cells, hence inhibiting EMT of these cells in vitro. [Copyright &y& Elsevier]

Immunogenic chemotherapy (IC) is a type of chemotherapy where certain chemodrugs induce immunogenic cancer cell death (ICD), which in turn arouses T cell antitumor immunity. However, IC concurrently upregulates a key immune suppressor, indoleamine-2,3-dioxygenase (IDO), in both cancer cells and immune cells. IDO-mediated immunosuppression significantly offsets IC's therapeutic benefits in cancer patients, suggesting a necessity of combination with IDO inhibitors. Here, we report an enzyme-, pH-, and redox-triple-sensitive nanosystem using mesoporous silica nanoparticles (MSNs) as a core encapsulating doxorubicin (DOX, an immunogenic chemodrug); the core is coated with a shell (β -CD-PEI/Ge1MT) for co-delivering 1-methyl-D-tryptophan (1 MT, an IDO inhibitor). By using these responsivenesses sequentially triggering the release of 1 MT into tumor extracellular compartment and DOX into intracellular endo/lysosomal compartment, this nanosystem (DOX@GMTMSNs) precisely delivers the drugs to their target cells residing in different compartments. Released 1 MT uptake by IDO-expressing dendritic cells (DCs) and cancer cells suppresses IDO activity, reducing immunosuppressive Tregs' presence; DOX unloaded within cancer cells induces ICD, promoting effector T-cell infiltration. In two preclinical cancer models, DOX@GMTMSNs potentiate both tumor local and systemic antitumor immunity, suppressing primary tumor growth by 78% with an 83% reduction in metastatic foci, as well as extending animal survival, thus strongly demonstrating DOX@ GMTMSNs' clinical translational potential. [ABSTRACT FROM AUTHOR]

To engineer tumor-tropic cells as drug delivery vehicles is a promising strategy to improve therapeutic specificity and efficacy for cancer treatment. However, conventional genetically engineered cell-based drug delivery systems are often capable of initiating single-mode therapy, and lack precise spatiotemporal control over the release of therapeutic payloads at tumor local, thus possibly causing severe systemic toxicity. Here, the macrophages are genetically engineered to encode a non-secreted form of EGFP-TNFα fusion protein and intracellularly carry near-infrared (NIR)-responsive heat-nanogenerators (HIMs). Owing to macrophages' intrinsic tumor tropism and HIMs' photo-responsiveness to NIR, these macrophages (HIMs@eMET) can actively accumulate at tumor sites and undergo controlled photothermolysis induced by NIR-induced HIMs-mediated photothermal effects (PTE). Such heat-induced cell explosion enables spatiotemporally controlled release of non-secreted TNFα from macrophages and effectively kills cancer cells. Importantly, in a preclinical tumor model, HIMs@eMET actively migrate to tumors where PTE and released EGFP-TNFα exhibit an enhanced antitumor effect, suppressing tumor growth and significantly prolonging animal survival without eliciting adverse side effects. Thus, this study demonstrates the potential of such dual-engineered macrophages in bi-modal cancer therapy. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) is a key issue accounting for ineffectiveness of cancer chemotherapy. Numerous multifunctional nanocarriers have been developed to increase drug delivery efficacy and inhibit drug efflux for overcoming cancer drug resistance. However, limited success has been achieved in clinic because of nanocarriers' complicated multi-step fabrication procedures and their undesired side toxicity as well as potential immunogenicity. Here, hyaluronic acid (HA) functionalized extracellular vesicles (EVs) are generated as natural vehicles to efficiently deliver doxorubicin (DOX) and reverse MDR. The EVs isolated from noncancerous HEK293T cells (hEVs) reduce P-glycoprotein (P-gp) expression in drug resistant MCF7/ADR cells. To acquire tumor-targeting capability, hEVs are modified with lipidomimetic chains-grafted HA (lipHA) by a simple incubation. Owing to CD44-mediated cancer-specific targeting and P-gp suppressive capability, the HA-functionalized hEVs (lipHA-hEVs) remarkably promote the intracellular DOX accumulation in drug resistant breast cancer cells. In preclinical MDR tumor models, lipHA-hEVs deeply penetrate into tumor tissue and effectively transport DOX into tumor local, while eliminating DOX's systemic toxicity. Importantly, DOX@lipHA-hEVs inhibited MDR tumor growth by 89% and extend animal survival time by approximately 50%. Thus, our engineered tumor-targeting hEVs are promising natural carriers for overcoming cancer MDR. [ABSTRACT FROM AUTHOR]