Abstract 5-Fluorouracil (5-FU) is known as a first-line chemotherapeutic agent against colorectal cancer (CRC), but drug resistance occurs frequently and significantly limits its clinical success. Our previous study showed that the protocadherin 17 ( PCDH17 ) gene was frequently methylated and functioned as a tumor suppressor in CRC. However, the relationship between PCDH17 and 5-FU resistance in CRC remains unclear. Here, we revealed that PCDH17 was more highly expressed in 5-FU-sensitive CRC tissues than in 5-FU-resistant CRC tissues, and high expression of PCDH17 was correlated with high BECN1 expression. Moreover, this expression profile contributed to superior prognosis and increased survival in CRC patients. Restoring PCDH17 expression augmented the 5-FU sensitivity of CRC in vitro and in vivo by promoting apoptosis and autophagic cell death. Furthermore, autophagy played a dominant role in PCDH17 -induced cell death, as an autophagy inhibitor blocked cell death to a greater extent than the pancaspase inhibitor Z-VAD-FMK. PCDH17 inhibition by siRNA decreased the autophagy response and 5-FU sensitivity. Mechanistically, we showed that c-Jun NH2-terminal kinase (JNK) activation was a key determinant in PCDH17 -induced autophagy. The compound SP600125, an inhibitor of JNK, suppressed autophagy and 5-FU-induced cell death in PCDH17 -reexpressing CRC cells. Taken together, our findings suggest for the first time that PCDH17 increases the sensitivity of CRC to 5-FU treatment by inducing apoptosis and JNK-dependent autophagic cell death. PCDH17 may be a potential prognostic marker for predicting 5-FU sensitivity in CRC patients.
Baicalin, as a natural active ingredient extracted and isolated from the traditional Chinese medicine Scutellaria baicalensis Georgi., has been potentially used in various areas for its antioxidative, antitumor, anti-inflammatory, and anti-proliferative activities. Although several studies have reported the antitumor effects of baicalin against various cancer types, its beneficial effects on lung cancer have not yet been elucidated. Therefore, the therapeutic effects and molecular mechanisms of baicalin on lung cancer cell lines H1299 and H1650 were investigated. Here, the results of its antitumor activity were shown. We found that Akt/mTOR pathway inhibition was the essential determinant in baicalin-induced cell cycle arrest. Furthermore, when the Akt Agonist SC79 or Akt plasmid transfection was performed, the antitumor effect of baicalin was significantly abrogated in both H1299 and H1650 cells. In conclusion, we found that baicalin exerted its antitumor activity mainly by inducing Akt-dependent cell cycle arrest and promoting apoptosis, which show great potential for developing a new drug for lung cancer treatment.
Accumulating evidence suggests that chronic inflammation may play a critical role in various malignancies, including bladder cancer. This hypothesis stems in part from inflammatory cells observed in the urethral microenvironment. Chronic inflammation may drive neoplastic transformation and the progression of bladder cancer by activating a series of inflammatory molecules and signals. Recently, it has been shown that the microbiome also plays an important role in the development and progression of bladder cancer, which can be mediated through the stimulation of chronic inflammation. In effect, the urinary microbiome can play a role in establishing the inflammatory urethral microenvironment that may facilitate the development and progression of bladder cancer. In other words, chronic inflammation caused by the urinary microbiome may promote the initiation and progression of bladder cancer. Here, we provide a detailed and comprehensive account of the link between chronic inflammation, the microbiome and bladder cancer. Finally, we highlight that targeting the urinary microbiome might enable the development of strategies for bladder cancer prevention and personalized treatment.
Abstract Background Type 1 diabetes is believed to be an autoimmune condition, characterized by destruction of insulin-producing cells, due to the detrimental inflammation in pancreas. Growing evidences have indicated the important role of type I interferon in the development of type 1 diabetes. Methods Trex1 -deficient rats were generated by using CRISPR-Cas9. The fasting blood glucose level of rat was measured by a Roche Accuchek blood glucose monitor. The levels of insulin, islet autoantibodies, and interferon-β were measured using enzyme-linked immunosorbent assay. The inflammatory genes were detected by quantitative PCR and RNA-seq. Hematein-eosin staining was used to detect the pathological changes in pancreas, eye and kidney. The pathological features of kidney were also detected by Masson trichrome and periodic acid-Schiff staining. The distribution of islet cells, immune cells or ssDNA in pancreas was analyzed by immunofluorescent staining. Results In this study, we established a Trex1 -deletion Sprague Dawley rat model, and unexpectedly, we found that the Trex1 −/− rats spontaneously develop type 1 diabetes. Similar to human diabetes, the hyperglycemia in rats is accompanied by diabetic complications such as diabetic nephropathy and cataract. Mechanistical investigation revealed the accumulation of ssDNA and the excessive production of proinflammatory cytokines, including IFN-β, in Trex1 null pancreas. These are likely contributing to the inflammation in pancreas and eventually leading to the decline of pancreatic β cells. Conclusions Our study links the DNA-induced chronic inflammation to the pathogenesis of type 1 diabetes, and also provides an animal model for type 1 diabetes studies.
Cancer incidence and mortality are rapidly growing around the world. As a noninvasive strategy for cancer treatment, photothermal therapy (PTT) utilizes near-infrared (NIR) light absorbents to produce local hyperpyrexia from light energy, resulting in the thermal elimination of tumors. Different nanostructures that possess strong absorbance of NIR light have been exploited as photothermal agents (PTAs) that need to be biodegradable and have strong optical absorbance in the NIR optical window. However, it remains highly challenging to identify the small molecule-based photothermal agents with a high photothermal conversion efficiency (PCE). Therefore, various types of PTAs have been developed in the last decades. These PTAs usually absorb NIR light where the living cells exhibit no absorption and autofluorescence and are able to transit absorption light to heat energy. Based on previous reports, the synthesized PTAs can be classified into two types: Inorganic nanomaterials and organic small molecular nanomaterials. Recently, for the first time, we demonstrated the synthesis of two dimensional (2D) monoelemental germanene quantum dots (GeQDs) through a facile liquid exfoliation method for photonic cancer nanomedicine. Our research can solve the major problem that 2D materials are difficultly synthetized and traditional materials have low photothermal conversion efficiency. Currently, photothermal therapy is a new type of highly effective, non-invasive and highly targeted therapy for cancer, however, the high temperature induced by PTT may also cause serious damage to healthy tissues. Therefore, mild photothermal therapy (MPTT) with relatively low temperature has attracted more and more attention. Due to the limited antitumor effect of MPTT, it is usually combined with other strategies to synergistically eliminate cancer cells. MPTT nanoplatform with enhanced curative efficacy and lower side effect is promising to apply in the field of drug controlled release, imaging-guided cancer treatment, and integrated therapy with other anticancer approaches. In this review, we briefly introduce the types and characteristics of PTAs, their anticancer function and the combined strategies for cancer therapy. Finally, we discuss the role of MPTT as a promising new therapeutic strategy for cancer therapy.
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Abstract Purpose To evaluate the relationship between the DNA mismatch repair (MMR) status and histone lysine‐specific demethylase 6A (KDM6A) on the prognosis of colorectal cancer (CRC). Methods About 594 patients with CRC from The Cancer Genome Atlas (TCGA) were enrolled in this retrospective study. Subsequently, a series of different classification tests for MMR status, cancer types, and target gene expression was conducted. Results After filtering out the KDMs group of genes, we selected KDM6A as the target gene. A significant difference in the performance of KDM6A in tumor and normal tissues were confirmed. Our results showed a lower KDM6A expression, lower KDM6A exon expression, and higher KDM6A DNA methylation than their corresponding normal tissues in colon adenocarcinoma (COAD). Notably, the main MMR genes were highly expressed in tumor tissues than normal tissues both in COAD and rectum adenocarcinoma (READ). Moreover, proficient DNA mismatch repair (pMMR) was found to be an important poor prognostic factor in COAD ( p = 0.0064) and the low KDM6A expression was an important factor for poor prognosis in READ ( p = 0.0217). Based on these results, we consequently relate MMR status with KDM6A expression in predicting the prognosis of patients with CRC. Moreover, patients with pMMR exhibited a low KDM6A expression in COAD ( p = 0.0250). Samples were divided into two groups based on the KDM6A expression. Interestingly, the group with low KDM6A expression showed no difference between pMMR and deficient DNA mismatch repair (dMMR) in prognosis, whereas the group with high KDM6A expression was closely related to MMR status in OS ( p = 0.0082). Besides, COAD patients with high KDM6A expression and pMMR status had poor OS ( p = 0.0082). Conclusions The KDM6A/MMR classification‐based subtypes of low KDM6A expression/READ, high KDM6A expression/pMMR, and COAD/pMMR were associated with poor prognosis. This classification can be a novel prognostic approach in CRC.
Background and Purpose: RAS mutations limit the effectiveness of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in combination with chemotherapy for metastatic colorectal cancer (mCRC) patients. Therefore, new cell death forms have focused on identifying indirect targets to inhibit Ras-induced oncogenesis. Recently, emerging evidence has shown the potential of triggering ferroptosis for cancer therapy, particularly for eradicating aggressive malignancies that are resistant to traditional therapies. Methods: KRAS mutant CRC cell HCT116 and Lovo were treated with cetuximab and β-elemene, a bioactive compound isolated from Chinese herb Curcumae Rhizoma. Ferroptosis and epithelial-mesenchymal transformation (EMT) were detected in vitro and in vivo. Orthotopic CRC animal model were established and the tumor growth was monitored by IVIS bioluminescence imaging. Tumor tissues were collected to determine ferroptosis effect and the expression of EMT markers after the treatment. Results: CCK-8 assay showed that synergetic effect was obtained when 125 µg/ml β-elemene was combined with 25 µg/ml cetuximab in KRAS mutant CRC cells. AV/PI staining suggested a non-apoptotic mode of cell death after the treatment with β-elemene and cetuximab. In vitro, β-elemene in combination with cetuximab was shown to induce iron-dependent reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, lipid peroxidation, upregulation of HO-1 and transferrin, and downregulation of negative regulatory proteins for ferroptosis (GPX4, SLC7A11, FTH1, glutaminase, and SLC40A1) in KRAS mutant CRC cells. Meanwhile, combinative treatment of β-elemene and cetuximab inhibited cell migration and decreased the expression of mesenchymal markers (Vimentin, N-cadherin, Slug, Snail and MMP-9), but promoted the expression of epithelial marker E-cadherin. Moreover, ferroptosis inhibitors but not other cell death suppressors abrogated the effect of β-elemene in combination with cetuximab on KRAS mutant CRC cells. In vivo, co-treatment with β-elemene and cetuximab inhibited KRAS mutant tumor growth and lymph nodes metastases. Conclusions: Our data for the first time suggest that the natural product β-elemene is a new ferroptosis inducer and combinative treatment of β-elemene and cetuximab is sensitive to KRAS mutant CRC cells by inducing ferroptosis and inhibiting EMT, which will hopefully provide a prospective strategy for CRC patients with RAS mutations.
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