Comparative Study of Short-Term Efficacy and Safety of Radical Surgery with or without Hyperthermic Intraperitoneal Chemotherapy in Colorectal Cancer with T4 Stage: A Propensity Score Matching Analysis.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) in T4 colorectal cancer (CRC) remains controversial. The study aimed to explore the safety and efficacy of radical surgery (RS) with HIPEC in T4 CRC. METHODS: Adverse events after HIPEC were estimated by Common Terminology Criteria for Adverse Events version 5.0. The efficacy was evaluated using recurrence-free survival (RFS) and overall survival (OS). Propensity score matching (PSM) was used to reduce the effects of confounders between groups. RESULTS: Of the 417 patients (263 men and 154 women), 165 patients were treated with RS + HIPEC and 252 patients with RS alone. There was no significant difference in the incidence of all adverse events after PSM. Overall RFS and OS were not significantly different at 24 months (p = 0.580 and p = 0.072, respectively). However, in patients with T4b stage CRC (92.1% vs. 77.3%, p = 0.048) and tumor size ≥ 5 cm (93.0% vs. 80.9%, p = 0.029), RFS in the two groups showed a significant difference at 24 months. CONCLUSIONS: In summary, the safety of HIPEC in T4 CRC was confirmed. Compared with RS, though RS + HIPEC did not benefit the overall cohort at 24 months, RS + HIPEC could benefit patients with T4b stage CRC and tumor size ≥ 5 cm in RFS.

Comparative Study of Short-Term Efficacy and Safety of Mitomycin versus Lobaplatin for Hyperthermic Intraperitoneal Chemotherapy after Radical Surgery in Colorectal Cancer with High-Risk Factors for Peritoneal Carcinomatosis: A Propensity Score Matching Analysis.

BACKGROUND: The drug selection of radical surgery (RS), with hyperthermic intraperitoneal chemotherapy (HIPEC), in pT4 colorectal cancer (CRC) remains controversial. METHODS: Adverse events after HIPEC were estimated by common terminology criteria for adverse events version 5.0. The efficacy was evaluated using overall survival (OS) and recurrence-free rate (RFR). Propensity score matching (PSM) was used to reduce the influence of confounders between Mitomycin and Lobaplatin groups. RESULTS: Of the 146 patients, from April 2020 to March 2021, 47 were managed with mitomycin and 99 with lobaplatin. There was no significant difference in the incidence of all adverse events between the two groups after PSM. OS and RFR were not significantly different between the two groups at 22 months (p = 0.410; p = 0.310). OS and RFR of the two groups also showed no significant difference for patients with T4a or T4b stage, tumor size < or ≥ 5 cm. Among patients with colon cancer, RFR at 22 months of the two groups was significantly different (100.0% vs. 63.2%, p = 0.028). CONCLUSIONS: In summary, the safety of mitomycin and lobaplatin for HIPEC was not different. Compared with lobaplatin, mitomycin for HIPEC after RS could benefit patients with colon cancer in RFR.

Exosome-Delivered circSTAU2 Inhibits the Progression of Gastric Cancer by Targeting the miR-589/CAPZA1 Axis.

Background: Circular RNAs (circRNAs) are endogenous noncoding RNAs that play vital roles in many biological processes, particularly in human cancer. Recent studies indicate that circRNAs play an important role in tumor progression through exosomes. However, the specific functions of gastric cancer-derived exosomes and the role of circSTAU2 in gastric cancer (GC) remain largely unknown. Methods: Differentially expressed circRNAs in GC were identified by circRNA microarrays analysis and quantitative real-time polymerase chain reaction (qRT-PCR). The role of circSTAU2 in GC was verified by circSTAU2 knockdown and overexpression with functional assays both in vitro and in vivo. Fluorescence in situ hybridization (FISH), immunofluorescence, RNA immunoprecipitation (RIP), dual-luciferase reporter assay, qRT-PCR and Western blot were adopted to evaluate the expression and regulatory mechanism of MBNL1, circSTAU2, miR-589 and CAPZA1. Furthermore, the role of exosomes was demonstrated by transmission electron microscopy and nano-sight particle tracking analysis. Results: CircSTAU2, mainly localized in the cytoplasm, was significantly downregulated in GC. CircSTAU2 overexpression inhibited GC cell proliferation, invasion and migration both in vitro and in vivo, while circSTAU2 knockdown had the inverse effect. CircSTAU2 could be wrapped in exosomes and delivered to recipient cells, and functioned as a sponge for miR-589 to relieve its inhibitory effect on CAPZA1, thus inhibiting GC progression. Furthermore, MBNL1 acted as the upstream RNA-binding protein of circSTAU2 and significantly influenced the circularization and expression of circSTAU2. Conclusion: Exosome-delivered circSTAU2 may act as a tumor suppressor that restrains GC progression via miR-589/CAPZA1 axis, which demonstrates a potential therapeutic target for GC.

Centrosomal protein 120 promotes centrosome amplification and gastric cancer progression via USP54-mediated deubiquitination of PLK4.

Centrosomal protein 120 (CEP120) is a 120 kDa centrosome protein that plays an important role in centrosome replication. Overexpression of CEP120 can lead to centrosome duplicate abnormality, which is closely associated with tumorigenesis and development. However, there are no reports on the relationship between CEP120 and tumors. In our study, overexpression of CEP120 promoted centrosome amplification in gastric cancer (GC), and the role of CEP120 in promoting GC progression was demonstrated in vitro and in vivo. We demonstrated that CEP120 promotes centrosome amplification and GC progression by promoting the expression and centrosome aggregation of the deubiquitinating enzyme USP54, maintaining the stability of PLK4 and reducing its ubiquitination degradation. In conclusion, the CEP120-USP54-PLK4 axis may play an important role in promoting centrosome amplification and GC progression, thus providing a potential therapeutic target for GC.

Mist1+ gastric isthmus stem cells are regulated by Wnt5a and expand in response to injury and inflammation in mice.

BACKGROUND AND AIMS: The gastric epithelium undergoes continuous turnover. Corpus epithelial stem cells located in the gastric isthmus serve as a source of tissue self-renewal. We recently identified the transcription factor Mist1 as a marker for this corpus stem cell population that can give rise to cancer. The aim here was to investigate the regulation of the Mist1+ stem cells in the response to gastric injury and inflammation. METHODS: We used Mist1CreERT;R26-Tdtomato mice in two models of injury and inflammation: the acetic acid-induced ulcer and infection with Helicobacter felis. We analysed lineage tracing at both early (7 to 30 days) and late (30 to 90 days) time points. Mist1CreERT;R26-Tdtomato;Lgr5DTR-eGFP mice were used to ablate the corpus basal Lgr5+ cell population. Constitutional and conditional Wnt5a knockout mice were used to investigate the role of Wnt5a in wound repair and lineage tracing from the Mist1+ stem cells. RESULTS: In both models of gastric injury, Mist1+ isthmus stem cells more rapidly proliferate and trace entire gastric glands compared with the normal state. In regenerating tissue, the number of traced gastric chief cells was significantly reduced, and ablation of Lgr5+ chief cells did not affect Mist1-derived lineage tracing and tissue regeneration. Genetic deletion of Wnt5a impaired proliferation in the gastric isthmus and lineage tracing from Mist1+ stem cells. Similarly, depletion of innate lymphoid cells, the main source of Wnt5a, also resulted in reduced proliferation and Mist1+ isthmus cell tracing. CONCLUSION: Gastric Mist1+ isthmus cells are the main supplier of regenerated glands and are activated in part through Wnt5a pathway.

Acute Intestinal Inflammation Depletes/Recruits Histamine-Expressing Myeloid Cells From the Bone Marrow Leading to Exhaustion of MB-HSCs.

BACKGROUND & AIMS: Histidine decarboxylase (HDC), the histamine-synthesizing enzyme, is expressed in a subset of myeloid cells but also marks quiescent myeloid-biased hematopoietic stem cells (MB-HSCs) that are activated upon myeloid demand injury. However, the role of MB-HSCs in dextran sulfate sodium (DSS)-induced acute colitis has not been addressed. METHODS: We investigated HDC+ MB-HSCs and myeloid cells by flow cytometry in acute intestinal inflammation by treating HDC-green fluorescent protein (GFP) male mice with 5% DSS at various time points. HDC+ myeloid cells in the colon also were analyzed by flow cytometry and immunofluorescence staining. Knockout of the HDC gene by using HDC-/-; HDC-GFP and ablation of HDC+ myeloid cells by using HDC-GFP; HDC-tamoxifen-inducible recombinase Cre system; diphtheria toxin receptor (DTR) mice was performed. The role of H2-receptor signaling in acute colitis was addressed by treatment of DSS-treated mice with the H2 agonist dimaprit dihydrochloride. Kaplan-Meier survival analysis was performed to assess the effect on survival. RESULTS: In acute colitis, rapid activation and expansion of MB-HSC from bone marrow was evident early on, followed by a gradual depletion, resulting in profound HSC exhaustion, accompanied by infiltration of the colon by increased HDC+ myeloid cells. Knockout of the HDC gene and ablation of HDC+ myeloid cells enhance the early depletion of HDC+ MB-HSC, and treatment with H2-receptor agonist ameliorates the depletion of MB-HSCs and resulted in significantly increased survival of HDC-GFP mice with acute colitis. CONCLUSIONS: Exhaustion of bone marrow MB-HSCs contributes to the progression of DSS-induced acute colitis, and preservation of quiescence of MB-HSCs by the H2-receptor agonist significantly enhances survival, suggesting the potential for therapeutic utility.

Expression of DCP1a in gastric cancer and its biological function and mechanism in chemotherapy resistance in gastric cancer cells.

AIMS: To detect the role of DCP1a in gastric cancer. To estimate the effect of DCP1a in gastric cancer cells on proliferation, invasion, migration and anti-drug behavior in vitro by down-regulating its expression. METHODS: Using IHC staining and Western blot to check the expression of DCP1a in tissues and the cell lines. SGC7901 and BGC823 cells were transfected with DCP1a siRNA, and the expression of DCP1a protein and mRNA were detected. The cell proliferation rate was detected by MTT assay and plate cloning assay. Transwell assay was used to detect the change of cell metastasis. The inhibition rates of cells to chemotherapy were detected by MTT assay. And signal pathways were also detected. RESULTS: The expression of DCP1a in cancer tissues is higher (p < 0.05), and higher expression of DCP1a is related to poor prognosis. After down-regulating the expression of DCP1a in cells, the proliferation rates, migration abilities and chemotherapy resistance decrease. We find that the expression of MRP-1 and the activation of AKT and STAT3 pathways might be involved in regulation. CONCLUSION: The high expression of DCP1a might be associated with cancer development and prognosis. Down-regulating the expression of DCP1a will help to reduce chemotherapy resistance, which will help with further improvement of chemotherapy in gastric cancer.

A Review of Research Progress in Multidrug-Resistance Mechanisms in Gastric Cancer.

Gastric cancer is one of the most common malignant tumors, and it is also one of the leading causes of cancer death worldwide. Because of its insidious symptoms and lack of early dictation screening, many cases of gastric cancer are at late stages which make it more complicated to cure. For these advanced-stage gastric cancers, combination therapy of surgery, chemotherapy, radiotherapy and target therapy would bring more benefit to the patients. However, the drug-resistance to the chemotherapy restricts its effect and might lead to treatment failure. In this review article, we discuss the mechanisms which have been found in recent years of drug resistance in gastric cancer. And we also want to find new approaches to counteract chemotherapy resistance and bring more benefits to the patients.

NFIB promotes cell growth, aggressiveness, metastasis and EMT of gastric cancer through the Akt/Stat3 signaling pathway.

Nuclear factor I/B (NFIB) plays a crucial role in the progression of several types of cancers. However, its role in gastric cancer (GC) remains unclear. The present study revealed that NFIB was highly expressed in GC tissues and was positively associated with the clinicopathological features of GC patients. Downregulation of NFIB inhibited the tumor growth, migration and aggression of MKN45 and HGC27 cells in vitro. In addition, NFIB expression promoted epithelial­mesenchymal transition (EMT), which was accompanied with decreased E­cadherin and increased vimentin expression. Since AKT and Stat3 play an important role in EMT and tumor progression, we examined whether there is a correlation between NFIB and AKT/Stat3 signaling pathways in GC. Our results revealed that NFIB exhibits its oncogenic functions in GC development by regulating the phosphorylation of both AKT and Stat3 molecules. Knocking down the NFIB expression may enhance the phosphorylation of AKT while inhibiting the Stat3 phosphorylation, suggesting that the AKT/Stat3 signaling pathway may be the downstream target of NFIB with which it exerts its roles on GC development. These results revealed that NFIB promotes tumor growth and aggressiveness of GC. In addition, downregulation of NFIB alters the protein kinase B/signal transducers and activators of transcription 3 (AKT/Stat3) axis, which could be a potential molecular mechanism for precise target treatment of GC.

MALAT1 promotes the colorectal cancer malignancy by increasing DCP1A expression and miR203 downregulation.

The long non-coding RNA MALAT1 has been proved to promote the cell proliferation, drug resistance, invasion, and metastasis of colorectal cancer (CRC) in vitro and in vivo by regulating the expression of various oncogenes and their protein products. Our previous work discovered that the expression of the mRNA-decapping enzymes 1a (DCP1A) is upregulated in CRCs. However, the relationships between MALAT1 and DCP1A in the development of CRC and the underlying mechanisms are still unclear. In this study, we investigated the molecular mechanisms by which MALAT1 and DCP1A may be linked to contribute to the malignancies of CRCs. We found that DCP1A is a direct target molecule of MALAT1. Moreover, by screening the downstream genes of MALAT1, we noticed that microRNA 203(miR203), an oncogene suppressor in numerous cancers, is inversely correlated to both MALAT1 and DCP1A expressions. Following MALAT1 knockdown, we observed overexpression of miR203 accompanied with DCP1A downregulation to a level that reversed the promoted cell proliferation, invasion, and migration in vitro and in vivo, which could be restored by miR203 knockdown or DCP1A overexpression. These results proposed a new molecular mechanism of MALAT-miR203-DCP1A axis which is involved with the development and contributes to the malignancy of colorectal cancers.

Overexpression of mRNA-decapping enzyme 1a affects survival rate in colorectal carcinoma.

Processing bodies (P-bodies) are one of the most well understood types of RNA granules, and are associated with a variety of diseases, including cancer. mRNA-decapping enzyme 1a (DCP1a), which may be used as a marker to analyze P-bodies, participates in the removal of the 5'-methylguanosine cap from eukaryotic mRNAs as a cofactor. The aim of the present study was to analyze the association between DCP1a expression and clinical features in colorectal carcinoma (CRC). The levels of DCP1a mRNA expression were detected by reverse transcription-quantitative polymerase chain reaction assay in carcinoma and non-carcinoma tissues from 75 patients, while the protein expression levels were evaluated by immunohistochemistry and western blotting. Additional associations between DCP1a expression and clinical characteristics were analyzed by χ2 test and Cox regression analysis. In the 75 cases, the levels of DCP1a mRNA and protein expression were increased in colorectal carcinoma tissues compared with non-carcinoma tissues. A high expression of DCP1a was significantly associated with lower survival rates in patients with CRC compared with patients with low DCP1a expression (P=0.001). Associations with depth of invasion (P=0.008), lymph node metastasis (P=0.001) and tumor node metastasis stage (P=0.001) were also observed. Additional Cox regression analysis revealed that the DCP1a expression (P=0.012) is an independent factor in survival rate. It was also identified that DCP1a may have high expression in colorectal carcinoma tissues and be associated with poor prognosis. This suggests that DCP1a may be a diagnostic marker or prognostic indicator to assist with patient assessments and therapies.

Effect and Mechanism of Curcumin on EZH2 - miR-101 Regulatory Feedback Loop in Multiple Myeloma.

BACKGROUND: Multiple myeloma is the second most prevalent hematologic malignancy and thought to be incurable. Therefore, it's urgent to find new drugs for treatment. Some experiments have shown that curcumin might have great potential in treating multiple myeloma, while the mechanism is still unknown. EZH2 and SUZ12 are the core proteins in PRC2 and their expressions are increased in various human cancers, including the poor prognostic multiple myeloma. Meanwhile, the regulation of miRNAs and EZH2 has been demonstrated in other cancer researches, like lung cancer, pancreatic cancer, leukemia and so on. OBJECTIVE: To reveal the mechanism behind the anti-tumor effect of cucurmin in multiple myeloma. METHOD: The effect of curcumin on the growth of MM cells was studied by MTT assay in the MM cell lines RPMI8226 and U266. Apoptosis was measured by Annexin V-FITC/PI double staining method. Western blotting, RT-PCR and luciferase activity assay were used to assess the expression of EZH2, SUZ12, miR-101 and downstream proteins such as E-cadherin, MMP9, c-Myc, cyclin D3, CDK4 and CDK6. RESULTS: Curcumin could significantly inhibite the proliferation of MM cells in a time- and concentrationdependent manner. Curcumin induced apoptosis by inhibiting the expression of EZH2, and the apoptosis rates were 16.42% and 25.62% when the RPMI8226 cells incubated with 5 and 10 µmol/L of curcumin. For U266 cells, the apoptosis rates were 15.25% and 21.28%. The up-regulation of miR-101 led to the lower expression of EZH2. In adverse, the expression of EZH2 induced lower expression of miR-101. The down-stream proteins of miR-101 were regulated by curcumin and EZH2 at the same time. CONCLUSION: Our experiments verified that the effect and mechanism of curcumin on multiple myeloma is via EZH2 - miR-101 regulatory feedback loop, which would lead us to a new way of investigating multiple myeloma and come up with new therapies in treating the disease.

Hedgehog signaling pathway in colorectal cancer: function, mechanism, and therapy.

Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide. It is a complicated and often fatal cancer, and is related to a high disease-related mortality. Around 90% of mortalities are caused by the metastasis of CRC. Current treatment statistics shows a less than 5% 5-year survival for patients with metastatic disease. The development and metastasis of CRC involve multiple factors and mechanisms. The Hedgehog (Hh) signaling plays an important role in embryogenesis and somatic development. Abnormal activation of the Hh pathway has been proven to be related to several types of human cancers. The role of Hh signaling in CRC, however, remains controversial. In this review, we will go through previous literature on the Hh signaling and its functions in the formation, proliferation, and metastasis of CRC. We will also discuss the potential of targeting Hh signaling pathway in the treatment, prognosis, and prevention of CRC.