KCTD15 acts as an anti-tumor factor in colorectal cancer cells downstream of the demethylase FTO and the m6A reader YTHDF2.

Potassium Channel Tetramerization Domain Containing 15 (KCTD15) participates in the carcinogenesis of several solid malignancies; however, its role in colorectal cancer (CRC) remains unclear. Here we find that KCTD15 exhibits lower expression in CRC tissues as compared to para-carcinoma tissues. Tetracycline (tet)-induced overexpression and knockdown of KCTD15 confirms KCTD15 as an anti-proliferative and pro-apoptotic factor in CRC both in vitro and in xenografted tumors. N6-methyladenosine (m6A) is known to affect the expression, stabilization, and degradation of RNAs with this modification. We demonstrate that upregulation of fat mass and obesity-associated protein (FTO), a classical m6A eraser, prevents KCTD15 mRNA degradation in CRC cells. Less KCTD15 RNA is recognized by m6A 'reader' YTH N6-Methyladenosine RNA Binding Protein F2 (YTHDF2) in FTO-overexpressed cells. Moreover, KCTD15 overexpression decreases protein expression of histone deacetylase 1 (HDAC1) but increases acetylation of critical tumor suppressor p53 at Lys373 and Lys382. Degradation of p53 is delayed in CRC cells post-KCTD15 overexpression. We further show that the regulatory effects of KCTD15 on p53 are HDAC1-dependent. Collectively, we conclude that KCTD15 functions as an anti-growth factor in CRC cells, and its expression is orchestrated by the FTO-YTHDF2 axis. Enhanced p53 protein stabilization may contribute to KCTD15's actions in CRC cells.

Sinomenine hydrochloride bidirectionally inhibits progression of tumor and autoimmune diseases by regulating AMPK pathway.

BACKGROUND: Chronic diseases such as tumors and autoimmune disorders are closely linked to metabolism and immunity and require conflicting treatment methods. AMPK can regulate cell growth and inflammation through energy metabolism. Sinomenine is a compound extracted from the traditional Chinese herb sinomenium acutum (Thunb.) Rehd. et Wils. It has been used to treat NSCLC (non-small-cell lung cancer) and RA (rheumatoid arthritis) in some studies, but with limited understanding of its mechanisms. OBJECTIVE: This study aims to examine the inhibitory effect of sinomenine hydrochloride (SH) on NSCLC and RA and to understand the underlying joint mechanisms. RESULTS: The results indicate that SH has a cytotoxic effect specifically on tumor cells, but not on normal cells. SH was found to induce cell apoptosis by activating the AMPK-mTOR pathway. Additionally, in autoimmune disease cell models, SH was shown to reduce the growth of RA-FLS cells by inhibiting the phosphorylation of AMPK, while having no effect on normal macrophages. Moreover, in vivo studies also showed that SH could reduce the production of pro-inflammatory cytokines such as TNF-α, IL-1ß, and IL-6 and slow the development of adjuvant arthritis in rats. Furthermore, SH was found to significantly suppress tumor growth in a tumor xenograft experiment in mice. CONCLUSIONS: This study provides new insights into the treatment of tumors and autoimmune diseases by demonstrating that SH can selectively inhibit the growth of NSCLC cells and the progression of RA through activation of the AMPK pathway.

Non-coding RNAs in metabolic reprogramming of bone and soft tissue sarcoma: Fundamental mechanism and clinical implication.

Sarcomas, comprising approximately 1% of human malignancies, show a poor response to treatment and easy recurrence. Metabolic reprogramming play an important role in tumor development in sarcomas. Accumulating evidence shows that non-coding RNAs (ncRNAs) participate in regulating the cellular metabolism of sarcomas, which improves the understanding of the development of therapy-resistant tumors. This review addresses the regulatory roles of metabolism-related ncRNAs and their implications for sarcoma initiation and progression. Dysregulation of metabolism-related ncRNAs is common in sarcomas and is associated with poor survival. Emerging studies show that abnormal expression of metabolism-related ncRNAs affects cellular metabolism, including glucose, lipid, and mitochondrial metabolism, and leads to the development of aggressive sarcomas. This review summarizes recent advances in the roles of dysregulated metabolism-related ncRNAs in sarcoma development and stemness and describes their potential to serve as biological biomarkers for disease diagnosis and prognosis prediction, as well as therapeutic targets for treating refractory sarcomas.

Non-coding RNAs in drug and radiation resistance of bone and soft-tissue sarcoma: a systematic review.

Background: Sarcomas comprise approximately 1% of all human malignancies; treatment resistance is one of the major reasons for the poor prognosis of sarcomas. Accumulating evidence suggests that non-coding RNAs (ncRNAs), including miRNAs, long ncRNAs, and circular RNAs, are important molecules involved in the crosstalk between resistance to chemotherapy, targeted therapy, and radiotherapy via various pathways. Methods: We searched the PubMed (MEDLINE) database for articles regarding sarcoma-associated ncRNAs from inception to August 17, 2022. Studies investigating the roles of host-derived miRNAs, long ncRNAs, and circular RNAs in sarcoma were included. Data relating to the roles of ncRNAs in therapeutic regulation and their applicability as biomarkers for predicting the therapeutic response of sarcomas were extracted. Two independent researchers assessed the quality of the studies using the Würzburg Methodological Quality Score (W-MeQS). Results: Observational studies revealed the ectopic expression of ncRNAs in sarcoma patients who had different responses to antitumor treatments. Experimental studies have confirmed crosstalk between cellular pathways pertinent to chemotherapy, targeted therapy, and radiotherapy resistance. Of the included studies, W-MeQS scores ranged from 3 to 10 (average score = 5.42). Of the 12 articles that investigated ncRNAs as biomarkers, none included a validation cohort. Selective reporting of the sensitivity, specificity, and receiver operating curves was common. Conclusions: Although ncRNAs appear to be good candidates as biomarkers for predicting treatment response and therapeutics for sarcoma, their differential expression across tissues complicates their application. Further research regarding their potential for inhibiting or activating these regulatory molecules to reverse treatment resistance may be useful. Funding: This study's literature retrieval was supported financially by the 345 Talent Project of Shengjing Hospital of China Medical University (M0949 to Tao Zhang).

Current status of neoadjuvant therapy for locally advanced rectal cancer in Wuhan Union Hospital Cancer Center.

BACKGROUND: To analyze and explore the evolution and short-term efficacy of neoadjuvant therapy for patients with mid and low LARC in Wuhan Union Hospital Cancer Center. METHODS: Patients diagnosed with rectal cancer from January 2015 to December 2021 were collected. The treatment patterns, short-term efficacy and treatment-related adverse events (AEs) of mid and low LARC patients who received neoadjuvant therapy were analyzed. The Chi-square test was used to compare the differences between groups. RESULTS: A total of 980 patients with mid and low LARC were enrolled, over time, the proportion of patients receiving neoadjuvant therapy gradually increased, and the treatment mode of direct surgery after diagnosis was gradually watered down. More than 80% of the patients implemented radiotherapy-based neoadjuvant therapy, and the proportion of patients receiving SCRT sequential systemic therapy gradually exceeded that of LCRT combined chemotherapy after 2020. Of all patients who completed radiotherapy and underwent surgery, 170 patients received long-course chemoradiotherapy (LCRT) combined with chemotherapy (Group C) and 98 patients received short-course radiotherapy (SCRT) combined with systemic therapy (chemotherapy with or without immunotherapy) (Group D). The pathological complete response (pCR) rate in Group D was significantly higher than that in Group C (38.8% vs. 19.4%, P = 0.001). The pCR rate in the SCRT plus immunotherapy group was better than that in the group without immunotherapy (49.2% vs. 21.6%, P = 0.007). 82.3% of the patients receiving immunotherapy were treated with SCRT sequential 2-cycle CapOX plus Camrelizumab treatment, and the pCR was as high as 52.9%. Immunotherapy did not increase the incidence of Grade 3-4 AEs. CONCLUSIONS: Neoadjuvant therapy based on radiotherapy is becoming used in patients with mid and low LARC. SCRT sequential systemic therapy is increasingly widely used in LARC patients in our center. Compared with the traditional LCRT or SCRT sequential chemotherapy, SCRT sequential chemotherapy plus immunotherapy has a remarkable pCR rate and manageable toxicity. Looking forward this new treatment mode will bring lasting survival benefits to patients.

Silencing of SBF2-AS1 inhibits cell growth and invasion by sponging microRNA-338-3p in serous ovarian carcinoma.

Long noncoding RNA SET-binding factor 2 (SBF2) antisense RNA 1 (AS1) is associated with the growth and metastasis of multiple cancer types, but its biological roles in serous ovarian carcinoma (SOC) remain unclear. In this study, the aberrant upregulation of SBF2-AS1 is detected in SOC after analysis of differentially expressed genes between SOC tissues and normal fallopian tubes from the public Gene Expression Omnibus (GEO) database. We determine that knockdown of SBF2-AS1 inhibits SOC cell proliferation and invasion by sponging miR-338-3p. MiR-338-3p acts as a tumor suppressor in SOC, and E26 transformation specific-1 (ETS1) is identified as a potential target of miR-338-3p regulation. Furthermore, SBF2-AS1 could modulate ETS1 by operating as a competing endogenous RNA for miR-338-3p. This finding elucidates a new mechanism for SBF2-AS1 in SOC development and provides a potential target for SOC therapeutic intervention.

A method establishment and comparison of in vivo lung cancer model development platforms for evaluation of tumour metabolism and pharmaceutical efficacy.

BACKGROUND: Currently, the identification of accurate biomarkers for the diagnosis of patients with early-stage lung cancer remains difficult. Fortunately, metabolomics technology can be used to improve the detection of plasma metabolic biomarkers for lung cancer. In a previous study, we successfully utilised machine learning methods to identify significant metabolic markers for early-stage lung cancer diagnosis. However, a related research platform for the investigation of tumour metabolism and drug efficacy is still lacking. HYPOTHESIS/PURPOSE: A novel methodology for the comprehensive evaluation of the internal tumour-metabolic profile and drug evaluation needs to be established. METHODS: The optimal location for tumour cell inoculation was identified in mouse chest for the non-traumatic orthotopic lung cancer mouse model. Microcomputed tomography (micro-CT) was applied to monitor lung tumour growth. Proscillaridin A (P.A) and cisplatin (CDDP) were utilised to verify the anti-lung cancer efficacy of the platform. The top five clinically valid biomarkers, including proline, L-kynurenine, spermidine, taurine and palmitoyl-L-carnitine, were selected as the evaluation indices to obtain a suitable lung cancer mouse model for clinical metabolomics research by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: The platform was successfully established, achieving 100% tumour development rate and 0% surgery mortality. P.A and CDDP had significant anti-lung cancer efficacy in the platform. Compared with the control group, four biomarkers in the orthotopic model and two biomarkers in the metastatic model had significantly higher abundance. Principal component analysis (PCA) showed a significant separation between the orthotopic/metastatic model and the control/subcutaneous/KRAS transgenic model. The platform was mainly involved in arginine and proline metabolism, tryptophan metabolism, and taurine and hypotaurine metabolism. CONCLUSION: This study is the first to simulate clinical metabolomics by comparing the metabolic phenotype of plasma in different lung cancer mouse models. We found that the orthotopic model was the most suitable for tumour metabolism. Furthermore, the anti-tumour drug efficacy was verified in the platform. The platform can very well match the clinical reality, providing better lung cancer diagnosis and securing more precise evidence for drug evaluation in the future.

Emodin induces apoptosis and suppresses non-small-cell lung cancer growth via downregulation of sPLA2-IIa.

BACKGROUND: Lung cancer has become the principal cause of cancer-related deaths. Emodin is a Chinese herb-derived compound extracted from the roots of Rheum officinale that exhibits numerous pharmacological characteristics. Secretory phospholipase A2-IIa (sPLA2-IIa) is overexpressed in cancers and plays an important role in cancer development. PURPOSE: This study aims to investigate the anti-tumor mechanism of emodin in non-small-cell lung cancer (NSCLC). METHODS: MTT assay was applied to detect the sensitivity of emodin to NSCLC cell line. Flow cytometry was used to examine the effect of emodin on cell cycle distribution and evaluate ROS level and apoptosis. Western blot analysis was utilised to examine the expression levels of sPLA2-IIa, PKM2, and AMPK and its downstream pathways induced by emodin. Enzyme inhibition assay was applied to investigate the inhibitory effect of emodin on sPLA2-IIa. The anticancer effect of emodin was also detected using an in vivo model. RESULTS: Emodin significantly inhibited NSCLC proliferation in vivo and in vitro and was relatively less cytotoxic to normal lung cell lines. Most importantly, emodin inhibited the proliferation of KRAS mutant cell lines by decreasing the expression of sPLA2-IIa and NF-κB pathways. Emodin also inhibited mTOR and AKT and activated the AMPK pathway. Furthermore, emodin induced apoptosis, increased the reactive oxygen species (ROS) level, and arrested the cell cycle. CONCLUSION: Emodin exhibited a novel anti-tumor mechanism of inhibiting the proliferation of KRAS mutant cell lines by decreasing the expression levels of sPLA2-IIa and NF-κB pathways. Hence, emodin can potentially serve as a therapeutic target in NSCLC.

[Paclitaxel liposome for the treatment of castration-resistant prostate cancer].

OBJECTIVE: To investigate the effect and safety of the 3-week paclitaxel liposome protocol in the treatment of castration-resistant prostate cancer (CRPC). METHODS: This retrospective study included 40 cases of CRPC treated by the 3-week paclitaxel liposome protocol from February 2014 to February 2019, which involved intravenous injection of 10 mg dexamethasone in 100 ml normal saline on the first day and that of metoclopramide and panxi tora azole on the second day, followed by about 3 hours of intravenous drip of paclitaxel liposome at 135 mg/m2 for a course of 3 weeks. During the follow-up period, the patients received detection of the serum PSA level before treatment and chest x-ray and whole-body bone scan every six months. After two courses of treatment, the patients were observed for the changes in the serum PSA level, relief of bone pain, quality of survival, overall survival rate, overall survival time and toxic reactions. The protocol was continued unless the patient underwent progression, refused for unacceptable toxicity, or died. RESULTS: The patients were aged 59 to 79 (mean 68.80±5.67) years old, with the serum PSA level of (28.05 ± 3.22) µg/L at the baseline and (4.12 ± 0.23) µg/L after treatment. Thirty-eight of the patients were followed up for 3 to 33 (mean 12.2) months. PSA-based evaluation showed therapeutic effectiveness in 14 cases (35%), stable condition in 21 (52.5 %) and progression in 5 (12.5 %). Of the 18 patients with bone metastasis and pain, 16 (88.9 %) experienced relief of the symptoms and reduced the use of painkillers, with the bone pain scores of 5.20 ± 1.22 vs 2.79 ± 0.57 before and after treatment. By the end of the follow-up, the overall survival rate was 55.0% (22/40) and the median survival time was 17 months (95% CI: 13.4－24.6). During the treatment, no obvious adverse reactions were observed except for anemia in 1 case and hair loss in another. CONCLUSIONS: For the treatment of CRPC in China, the 3-week paclitaxel liposome protocol has the advantages of desirable safety, low toxicity, acceptable drug tolerance and improved quality of survival, but its curative effect needs to be verified with more randomized clinical trials with larger samples and longer follow-ups.

Music interventions for chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is the most common and severe side effects brought by chemotherapeutics. The role of music interventions in relieving CINV is uncertain. The aim of this systematic review was to test the effects of music interventions on three categories of CINV. METHODS: A systematic search was conducted in Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), WanFang, and Chinese Biomedical Database (CBM) in order to capture randomized controlled trials (RCTs) investigating the comparative efficacy of music interventions and others. Two investigators screened, sorted, and extracted the data, and appraised the risk of bias. All statistical analyses were performed using RevMan 5.3 software. RESULTS: The literature search yielded 608 studies of which only ten RCTs fulfilled the eligibility criteria with 632 patients retrieved. Although the duration, the frequency of interventions, and the type of selected music varied across studies, commonly used elements included music listening. Results showed that music interventions were associated with reducing the incidence of anticipatory CINV and lowering the severity of delayed vomiting (MD = - 0.65, 95% CI = - 1.08 to - 0.23). However, strongly controversial results existed in terms of reducing the incidence of acute and delayed CINV, the severity of acute CINV, the severity of delayed nausea, and improving patients' quality of life. CONCLUSIONS: Music interventions may effectively reduce the incidence of anticipatory CINV and relieve the severity of delayed vomiting in patients with chemotherapy based on limited data. However, the conclusion should be interpreted with caution and further research is required to design with large-scale and rigorous methods.

A Risk Prediction Model for Breast Cancer Based on Immune Genes Related to Early Growth Response Proteins Family.

Early growth response proteins (EGRs), a transcriptional regulatory family comprised of EGR1, EGR2, EGR3, and EGR 4, are reportedly involved in a vast array of functions. However, EGRs, as a whole, are rarely studied in breast cancer cases. This research was performed based on public datasets. The results demonstrated that, except EGR4, the other EGRs were differentially expressed genes in breast cancer. Subsequently, this study determined the prognosis significance of the EGR family, higher expression levels of EGRs indicating better overall survival (OS) and disease-free survival (DFS), except EGR4. So we attempted to explore the potential mechanism behind the prognostic value of EGRs. At the DNA level, however, neither DNA methylation status nor genetic alterations of EGRs contributed to the prognosis significance. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that EGRs were involved in several immune-related functions. Afterward, we assessed the correlation between EGRs and the immune system before establishing a risk prediction model with a 14-gene immune signature associated with EGRs, a prognostic nomogram predicting individuals' 1-, 3-, and 5-year survival probabilities. The risk score was an independent prognosis predictor in the breast cancer cohorts. This study evidenced EGRs' significance for tumor immunity, demonstrating that the EGR family may be a potential immunotherapeutic target for breast cancer. The 14-gene immune signature is a promising prognostic biomarker in breast cancer.

[Molecular cloning and characterization of CMK from Artemisia annua].

Artemisinin is a preferred medicine in the treatment of malaria. In this study, AaCMK, a key gene involved in the upstream pathway of artemisinin biosynthesis, was cloned and characterized from Artemisia annua for the first time. The full-length cDNA of AaCMK was 1 462 bp and contained an ORF of 1 197 bp that encoded a 399-anomo-acid polypeptide. Tissue expression pattern analysis showed that AaCMK was expressed in leaves, flowers, roots and stems, but with higher expression level in glandular secretory trichomes. In addition, the expression of AaCMK was markedly increased after MeJA treatment. Subcellular localization showed that the protein encoded by AaCMK was localized in chloroplast. Overexpression of AaCMK in Arabidopsis increased the contents of chlorophyll a, chlorophyll b and carotenoids. These results suggest that AaCMK plays an important role in the biosynthesis of terpenoids in A. annua and this research provids a candidate gene that could be used for engineering the artemisinin biosynthesis.

Laparoscopic Low Anterior Resection of the Rectum with Transanal Prolapsing Specimen Extraction: Early Experience with 23 Patients.

OBJECTIVE: For laparoscopic low anterior resection of the rectum, a small additional incision is needed to extract the specimen. We describe an adjustment technique, which inserted the anvil and extracted the specimen through transanal pathway. METHODS: Between July 2010 and July 2012, 23 patients underwent laparoscopic rectal surgery with transanal anvil insertion and transanal prolapsing specimen extraction. All perioperative data and short-term outcomes were recorded in a database. RESULTS: The mean patient age was 61.3 years (range 47-68 years). Of the 23 patients, 17 underwent resection for rectal carcinoma and 6 had tubulovillous adenomas. No intraoperative complications occurred. The mean operative time was 137 minutes (range 118-170 minutes). The distal margins, circumferential resection margins, and lymph node dissections were oncologically adequate for all malignancies. One patient experienced anastomotic leakage (4.3%), treated conservatively. One male patient with benign prostatic hyperplasia suffered from postoperative urinary retention. The average postoperative hospital stay was 11.3 days (range 7-21 days). No patients experienced anal dysfunction. At a median follow-up of 26 months, there were no tumor recurrences. CONCLUSION: The technique of transanal prolapsing specimen extraction for laparoscopic low anterior resection of the rectum is feasible and safe for selected patients.

Overexpression of δ-catenin is associated with a malignant phenotype and poor prognosis in colorectal cancer.

Little is known regarding the expression or clinical significance of δ-catenin, a member of the catenin family, in colorectal cancer (CRC). The present study examined the expression of δ-catenin using immunohistochemistry in 110 cases of CRC, including 70 cases with complete follow­up records and 40 cases with paired lymph node metastases. In addition, δ­catenin mRNA and protein expression were compared in 30 pairs of matched CRC and normal colorectal tissues by reverse transcription quantitative polymerase chain reaction and western blot analysis. δ­Catenin was weakly expressed or absent in the cytoplasm of normal intestinal epithelial cells, whereas positive δ­catenin expression localized to the cytoplasm was observed in CRC cells. The rate of positive δ­catenin expression in CRC (68.18%; 75/110) was significantly higher than that in normal colorectal tissues (36.7%; 11/30; P<0.001). In addition, δ­catenin mRNA and protein expression were significantly increased in CRC tissues compared to those in their matched normal tissues (all P<0.05). The expression of δ­catenin in stage III­IV CRC was higher than that in stage I­II CRC, and the expression of δ­catenin in the tumors of patients with lymph node metastases was higher than that in patients without lymph node metastases. Kaplan­Meier survival curves demonstrated that the survival time of patients with positive δ­catenin expression was shorter than that of patients with negative δ­catenin expression (P=0.005). Furthermore, Cox multivariate analysis indicated that the tumor, nodes and metastasis stage (P=0.02) and positive δ-catenin expression (P=0.033) were independent prognostic factors in CRC. The present study therefore indicated that δ-catenin may be a suitable independent prognostic factor for CRC.

Delta-catenin promotes the proliferation and invasion of colorectal cancer cells by binding to E-cadherin in a competitive manner with p120 catenin.

δ-Catenin is the only member of the p120 catenin (p120ctn) subfamily whose normal pattern of expression is restricted to the brain. Similar to p120ctn, δ-catenin can bind to the juxtamembrane domain of E-cadherin. We examined the expression of δ-catenin, p120ctn, and E-cadherin using immunohistochemistry in 95 cases of colorectal cancer (CRC) and 15 normal colon tissues. Co-immunoprecipitation was used to examine whether δ-catenin competed with p120ctn to bind E-cadherin in CRC cells. The effects of δ-catenin overexpression or siRNA-mediated knockdown on the proliferation and invasive ability of CRC cells were investigated using the MTT and Matrigel invasion assays. The results showed that positive δ-catenin expression was significantly more frequent in CRC compared to normal colon tissues and associated with poor differentiation, stage III-IV disease, and lymph node metastasis in CRC (all P < 0.05). In two CRC cell lines, δ-catenin bound to E-cadherin in competition with p120ctn. Overexpression of δ-catenin promoted the proliferation and invasion of CRC cells; knockdown of δ-catenin reduced CRC cell proliferation and invasion. In conclusion, we speculate that overexpression of δ-catenin reduces the expression of E-cadherin and alters the balance between E-cadherin and p120ctn, which in turn affects the formation of intercellular adhesions and promotes invasion and metastasis in CRC.