RFC5, regulated by circ_0038985/miR-3614-5p, functions as an oncogene in the progression of colorectal cancer.

Replication factor C 5 (RFC5) is involved in a variety of biological functions of cancer. However, the expression pattern of RFC5 and the underlying mechanisms in colorectal cancer (CRC) remain elusive. Here, we show that RFC5 is significantly upregulated in CRC tissues and cells. Patients with CRC and increased RFC5 levels have an unfavorable prognosis. RFC5 can promote the proliferation, migration, and invasion of CRC cells and inhibit the apoptosis of CRC cells. Additionally, upstream of RFC5, we constructed the competing endogenous RNA network and confirmed that RFC5 in this network was inhibited by miR-3614-5p by directly targeting its 3'-untranslated regions. We verified that circ_0038985, which is positively correlated with RFC5, directly targeted miR-3614-5p. Overexpression of circ_0038985 promoted CRC cell migration and invasion, and these effects were partially reversed by the reintroduction of miR-3614-5p. Moreover, we found that RFC5 may promote the vascular endothelial growth factor A (VEGFa)/vascular endothelial growth factor receptor 2 (VEGFR2)/extracellular signal-regulated protein kinase (ERK) pathway. The knockdown of RFC5 reduced CRC tumorigenesis in vivo. Collectively, these data demonstrate that the circ_0038985/miR-3614-5p/RFC5 axis plays a critical role in the progression of CRC, and RFC5 may promote CRC progression by affecting the VEGFa/VEGFR2/ERK pathway.

A Longitudinal MRI-Based Artificial Intelligence System to Predict Pathological Complete Response After Neoadjuvant Therapy in Rectal Cancer: A Multicenter Validation Study.

BACKGROUND: Accurate prediction of response to neoadjuvant chemoradiotherapy is critical for subsequent treatment decisions for patients with locally advanced rectal cancer. OBJECTIVE: To develop and validate a deep learning model based on the comparison of paired MRI before and after neoadjuvant chemoradiotherapy to predict pathological complete response. DESIGN: By capturing the changes from MRI before and after neoadjuvant chemoradiotherapy in 638 patients, we trained a multitask deep learning model for response prediction (DeepRP-RC) that also allowed simultaneous segmentation. Its performance was independently tested in an internal and 3 external validation sets, and its prognostic value was also evaluated. SETTINGS: Multicenter study. PATIENTS: We retrospectively enrolled 1201 patients diagnosed with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy before total mesorectal excision. Patients had been treated at 1 of 4 hospitals in China between January 2013 and December 2020. MAIN OUTCOME MEASURES: The main outcome was the accuracy of predicting pathological complete response, measured as the area under receiver operating curve for the training and validation data sets. RESULTS: DeepRP-RC achieved high performance in predicting pathological complete response after neoadjuvant chemoradiotherapy, with area under the curve values of 0.969 (0.942-0.996), 0.946 (0.915-0.977), 0.943 (0.888-0.998), and 0.919 (0.840-0.997) for the internal and 3 external validation sets, respectively. DeepRP-RC performed similarly well in the subgroups defined by receipt of radiotherapy, tumor location, T/N stages before and after neoadjuvant chemoradiotherapy, and age. Compared with experienced radiologists, the model showed substantially higher performance in pathological complete response prediction. The model was also highly accurate in identifying the patients with poor response. Furthermore, the model was significantly associated with disease-free survival independent of clinicopathological variables. LIMITATIONS: This study was limited by its retrospective design and absence of multiethnic data. CONCLUSIONS: DeepRP-RC could be an accurate preoperative tool for pathological complete response prediction in rectal cancer after neoadjuvant chemoradiotherapy. UN SISTEMA DE IA BASADO EN RESONANCIA MAGNTICA LONGITUDINAL PARA PREDECIR LA RESPUESTA PATOLGICA COMPLETA DESPUS DE LA TERAPIA NEOADYUVANTE EN EL CNCER DE RECTO UN ESTUDIO DE VALIDACIN MULTICNTRICO: ANTECEDENTES:La predicción precisa de la respuesta a la quimiorradioterapia neoadyuvante es fundamental para las decisiones de tratamiento posteriores para los pacientes con cáncer de recto localmente avanzado.OBJETIVO:Desarrollar y validar un modelo de aprendizaje profundo basado en la comparación de resonancias magnéticas pareadas antes y después de la quimiorradioterapia neoadyuvante para predecir la respuesta patológica completa.DISEÑO:Al capturar los cambios de las imágenes de resonancia magnética antes y después de la quimiorradioterapia neoadyuvante en 638 pacientes, entrenamos un modelo de aprendizaje profundo multitarea para la predicción de respuesta (DeepRP-RC) que también permitió la segmentación simultánea. Su rendimiento se probó de forma independiente en un conjunto de validación interna y tres externas, y también se evaluó su valor pronóstico.ESCENARIO:Estudio multicéntrico.PACIENTES:Volvimos a incluir retrospectivamente a 1201 pacientes diagnosticados con cáncer de recto localmente avanzado y sometidos a quimiorradioterapia neoadyuvante antes de la escisión total del mesorrecto. Eran de cuatro hospitales en China en el período entre enero de 2013 y diciembre de 2020.PRINCIPALES MEDIDAS DE RESULTADO:Los principales resultados fueron la precisión de la predicción de la respuesta patológica completa, medida como el área bajo la curva operativa del receptor para los conjuntos de datos de entrenamiento y validación.RESULTADOS:DeepRP-RC logró un alto rendimiento en la predicción de la respuesta patológica completa después de la quimiorradioterapia neoadyuvante, con valores de área bajo la curva de 0,969 (0,942-0,996), 0,946 (0,915-0,977), 0,943 (0,888-0,998), y 0,919 (0,840-0,997) para los conjuntos de validación interna y las tres externas, respectivamente. DeepRP-RC se desempeñó de manera similar en los subgrupos definidos por la recepción de radioterapia, la ubicación del tumor, los estadios T/N antes y después de la quimiorradioterapia neoadyuvante y la edad. En comparación con los radiólogos experimentados, el modelo mostró un rendimiento sustancialmente mayor en la predicción de la respuesta patológica completa. El modelo también fue muy preciso en la identificación de los pacientes con mala respuesta. Además, el modelo se asoció significativamente con la supervivencia libre de enfermedad independientemente de las variables clinicopatológicas.LIMITACIONES:Este estudio estuvo limitado por el diseño retrospectivo y la ausencia de datos multiétnicos.CONCLUSIONES:DeepRP-RC podría servir como una herramienta preoperatoria precisa para la predicción de la respuesta patológica completa en el cáncer de recto después de la quimiorradioterapia neoadyuvante. (Traducción-Dr. Felipe Bellolio ).

MiR-15a-3p regulates ferroptosis via targeting glutathione peroxidase GPX4 in colorectal cancer.

Colorectal cancer (CRC) is the second most common cancer-related deaths throughout the world. Ferroptosis is a recently regulated form of cell death, lately gains attention. MicroRNA-15a-3p (miR-15a-3p) plays a regulatory role in various kinds of cancers. However, the role of miR-15a-3p in cellular ferroptosis is still unclear. Here, we aimed to clarify whether miR-15a-3p could regulate the ferroptosis of CRC. Here we identified miR-15a-3p positively regulates ferroptosis via directly targeting glutathione peroxidase glutathione peroxidase 4 (GPX4) in CRC. Overexpression of miR-15a-3p repressed GPX4 through binding to the 3'-untranslated region of GPX4, resulting in increased reactive oxygen species level, intracellular Fe2+ level, and malondialdehyde accumulation in vitro and in vivo. Correspondingly, suppression of miR-15a-3p reduced the sensitivity of CRC cells to erastin and GPX4. Taken together, these data demonstrate that miR-15a-3p regulates ferroptosis through targeting GPX4 in CRC cells, illustrating the novel role of microRNA in ferroptosis.

Tre2 (USP6NL) promotes colorectal cancer cell proliferation via Wnt/ß-catenin pathway.

BACKGROUND: Most colorectal cancer (CRC) patients are diagnosed at an advanced or metastatic stage with poor prognosis. Ubiquitin-specific protease 6 N-terminal-like protein (USP6NL) with high expression in CRC tissues regulates CRC cell proliferation via Wnt/ß-catenin pathway. We hypothesized that USP6NL impacts CRC growth and inhibition of USP6NL may be a novel treatment strategy to improve CRC therapy. METHODS: USP6NL level in human CRC tissues and its association with tumor growth and metastasis were examined. Its roles and potential mechanisms in regulating tumor growth were studied by genetic and pharmacological manipulation of CRC cells in vitro and in vivo. RESULTS: Herein, we found that USP6NL was up-regulated in tumorous tissues of CRC patients. Our data suggested that knockdown of USP6NL in human CRC cell lines (HCT116 and LOVO cells) inhibited cell proliferation, induced G0/G1 cell cycle arrest, and prevented the tumorigenicity of HCT116 cells in nude mice, and which was associated with the prevention of Wnt/ß-catenin pathway. On the contrary, USP6NL overexpression in human CRC cells (SW480) showed the opposite result. Our data suggested that the promoted cell proliferation, G1/S cell cycle progression, and the enhanced expression of ß-catenin Cyclin D1 and C-myc while reduced P27 induced by the overexpression of USP6NL were significantly reversed by additional treatment of XAV939, indicating that activating Wnt/ß-catenin pathway was the mechanism, by which USP6NL exerted carcinogenesis in CRC in vitro. Besides, our data suggested that knockdown of USP6NL increased the ubiquitination of ß-catenin, indicating that USP6NL may serve as a deubiquitinase that regulated ß-catenin accumulation in this process. Furthermore, 10058-F4 down-regulated USP6NL, inhibited CRC cell proliferation and induced cell cycle arrest. The result demonstrated a possible feedback loop between USP6NL, ß-catenin and C-myc in regulating CRC cell growth. CONCLUSION: USP6NL was an oncogene in CRC, and it may be a potential target for the treatment of CRC.

Variation and treatment of vessels in laparoscopic right hemicolectomy.

BACKGROUND: With the introduction of complete mesocolic excision (CME) and the application of laparoscopic technique, surgery for colon cancer has become more standardized and the curative effect has improved [1]. The key points in laparoscopic right hemicolectomy are high ligation of main vessels and root dissection of lymph nodes. The wide range of variations in vascular architecture and intraoperative bleeding are common causes of prolonged surgical time, wound hemorrhage, and even transfer to the opening operation. METHODS: The superior mesenteric vein (SMV) is the most important anatomical landmark in CME for the right colon, and guides all the steps of lymph node dissection. The SMV appears as a pale blue bulge on laparoscopy, which enables accurate positioning. The ileocolic vessel pedicle is relatively constant and facilitates accurate positioning. The intersection of the ileocolic vessel pedicle and the SMV is the optimal starting point in laparoscopic right hemicolectomy using a medial-to-lateral approach. A sheath with an avascular plane can be reached after opening the SMV vascular sheath, which results in less bleeding and enables vascular root and thorough lymph node dissection. The first step is to manage the ileocolic vessels. The ileocolic artery (ICA) is located anterior to the ileocolic vein (ICV) for about one-third of the incidence. The ileocolic vessels are relatively long and are easy to work with. In the vast majority of cases, the ICV drains into the SMV, and into the gastrocolic trunk (GCT) in about 2.5% of cases. The reported incidence of a right colic artery (RCA) is controversial; the RCA is absent in about 50% of cases and often crosses the SMV. The right colic vein (RCV) usually drains into the GCT, but sometimes drains directly into the SMV. The middle colic vessels have great variability and a close anatomical relationship with the pancreas, duodenum, and GCT. Moreover, the transverse colon and mesentery are long, and root positioning and processing of the middle colic vein (MCV) are relatively difficult. With the SMV and pancreas as anatomic landmarks, it is more feasible to locate the blood vessels in the neck of the pancreas. The middle colic artery (MCA) originates from the superior mesenteric artery (SMA), and the distance from the inferior border of the pancreas differs slightly in the literature, but is at the most 5 cm. Identification of the MCA trunk and branches, as well as the common origin of the MCA and RCA, is of great importance for the maintaining the blood supply during surgery for primary colon cancer. The MCV mainly drains into the SMV and GCT; however, if branching variation drains into the jejunal vein, inferior mesenteric vein, or splenic vein, the effect is serious when a vessel is torn. Isolation of the GCT is the step at which bleeding will likely occur in standard right resection and is a difficult stage of the surgery. The GCT has five origins including the right gastroepiploic vein (RGV), right colic vein (RCV), accessory right colic vein (ARCV), pancreaticduodenal vein (PDV), and MCV, which can have 2, 3, or 4 branches; therefore, familiarity with variants may be helpful to avoid bleeding. Approximately 5-10% of colon cancers at the hepatic flexure have No. 6 group lymph node metastasis, and laparoscopic radical extended right hemicolectomy requires thorough dissection of No. 6 group lymph nodes and the omental arcade 10 cm from the pylorus. The inferior arteriovenous vessels are a common source of bleeding, and the RGV can serve as a clue to finding the artery. CONCLUSIONS: The core area of laparoscopic radical extended right hemicolectomy includes the pancreatic neck, duodenum, and right gastroepiploic vessels. The difficulty lies with the standard treatment of the GCT. A medial-to-lateral approach is more in line with the principle of no-touch in tumor surgery and is applied from lower to upper, inside to outside, and left to right, for both the vessels and plane of dissection. Familiarity with vascular variation and the management of vessels in key areas are essential for successful surgery.

Circulating miR-1826 in plasma correlates with circulating tumor cells and is a prognostic marker in colorectal cancer.

Our previous study showed that miR-1826 was a newly identified oncogenic non-coding RNA in colorectal cancer. But the potential relationship between miR-1826 and tumor metastasis has not been fully elucidated. The purpose of this study was to evaluate the clinical significance of circulating miR-1826 and its possible associations with circulating tumor cells in colorectal cancer. Our results first found that serum miR-1826 was significantly upregulated in colorectal cancer patients, compared with that in healthy volunteers ( p = 0.003). Similar results were also found in colorectal cancer with distant metastasis ( p = 0.001) and advanced colorectal cancer ( p < 0.001) patients, respectively. Clinicopathological analysis implied that circulating miR-1826 was positively associated with pT stage ( p = 0.026), lymphatic metastasis ( p = 0.034), distant metastasis ( p = 0.012), and tumor-node-metastasis stage ( p = 0.020). Besides, our univariate and multivariate analyses demonstrated that high serum miR-1826 expression could act as a prognostic and independent factor for overall survival of colorectal cancer patients ( p < 0.05), which led to a poorer 5-year overall survival rate ( p = 0.025). The area under the curve value of circulating miR-1826 was up to 0.848 ± 0.043, which strongly suggested serum miR-1826 as an effective diagnostic biomarker in colorectal cancer patients ( p < 0.001). Our subsequent experiments demonstrated that patients with high level of circulating tumor cells showed a higher level of miR-1826 expression, compared with the circulating tumor cell-negative patients ( p = 0.011). Similar results also showed that the amount of circulating tumor cells in high miR-1826 group was significantly higher than that in low miR-1826 group ( p = 0.001). Furthermore, the relationship between serum miR-1826 and circulating tumor cells was analyzed using SPSS software and a significant logarithmic relationship was found, which meant that circulating miR-1826 closely correlated with the amount of circulating tumor cells in colorectal cancer patient serum ( r = 0.283, p < 0.01). Our findings strongly suggested that serum miR-1826 could serve as an effective and non-invasive biomarker for diagnosis and prognosis of colorectal cancer. Circulating miR-1826 may be an important target in colorectal cancer therapy.

Three-Dimensional Biologically Relevant Spectrum (BRS-3D): Shape Similarity Profile Based on PDB Ligands as Molecular Descriptors.

The crystallized ligands in the Protein Data Bank (PDB) can be treated as the inverse shapes of the active sites of corresponding proteins. Therefore, the shape similarity between a molecule and PDB ligands indicated the possibility of the molecule to bind with the targets. In this paper, we proposed a shape similarity profile that can be used as a molecular descriptor for ligand-based virtual screening. First, through three-dimensional (3D) structural clustering, 300 diverse ligands were extracted from the druggable protein-ligand database, sc-PDB. Then, each of the molecules under scrutiny was flexibly superimposed onto the 300 ligands. Superimpositions were scored by shape overlap and property similarity, producing a 300 dimensional similarity array termed the "Three-Dimensional Biologically Relevant Spectrum (BRS-3D)". Finally, quantitative or discriminant models were developed with the 300 dimensional descriptor using machine learning methods (support vector machine). The effectiveness of this approach was evaluated using 42 benchmark data sets from the G protein-coupled receptor (GPCR) ligand library and the GPCR decoy database (GLL/GDD). We compared the performance of BRS-3D with other 2D and 3D state-of-the-art molecular descriptors. The results showed that models built with BRS-3D performed best for most GLL/GDD data sets. We also applied BRS-3D in histone deacetylase 1 inhibitors screening and GPCR subtype selectivity prediction. The advantages and disadvantages of this approach are discussed.

Upregulated expression of miR-106a by DNA hypomethylation plays an oncogenic role in hepatocellular carcinoma.

Aberrant microRNA (miRNA) expression has been widely recognized to play an extremely important role in several cancers, including hepatocellular carcinoma (HCC). According to the previous studies, abnormal miR-106a expression was closely related to various cancer occurrences. However, the miR-106a expression in HCC remains unclear. In our study, we firstly detected the miR-106a expression levels in 36 pairs of HCC tissues. The results showed that miR-106a expression in HCC tissues was apparently higher than the level in the adjacent tissues. Then, we used quantitative real-time PCR (qPCR) and BSP to analyze miR-106a expression and promoter methylation in HCC cell lines. There came to a conclusion that the methylation status of the miR-106a promoter region was inversely correlated with the expression of miR-106a. After prediction with online software, we further used dual-luciferase reporter gene assay to ensure that TP53INP1 and CDKN1A might be the direct targets of miR-106a. At last, we explored the functions of miR-106a in HCC cells in vitro. Our results manifested that high-miR-106a cell line had stronger invasiveness, faster cell cycle progression, and more resistance to apoptosis compared with the low-miR-106a cell line. Therefore, our study suggested that upregulated expression of miR-106a by its promoter hypomethylation might contribute to the progression of HCC, which might be considered as a potentially effective biomarker and therapeutic approach in the future.

VMP1 related autophagy and apoptosis in colorectal cancer cells: VMP1 regulates cell death.

Vacuole membrane protein 1 (VMP1) is an autophagy-related protein and identified as a key regulator of autophagy in recent years. In pancreatic cell lines, VMP1-dependent autophagy has been linked to positive regulation of apoptosis. However, there are no published reports on the role of VMP1 in autophagy and apoptosis in colorectal cancers. Therefore, to address this gap of knowledge, we decided to interrogate regulation of autophagy and apoptosis by VMP1. We have studied the induction of autophagy by starvation and rapamycin treatment in colorectal cell lines using electron microscopy, immunofluorescence, and immunoblotting. We found that starvation-induced autophagy correlated with an increase in VMP1 expression, that VMP1 interacted with BECLIN1, and that siRNA mediated down-regulation of VMP1-reduced autophagy. Next, we examined the relationship between VMP1-dependent autophagy and apoptosis and found that VMP1 down-regulation sensitizes cells to apoptosis and that agents that induce apoptosis down-regulate VMP1. In conclusion, similar to its reported role in other cell types, VMP1 is an important regulator of autophagy in colorectal cell lines. However, in contrast to its role in pancreatic cell lines, in colorectal cancer cells, VMP1-dependent autophagy appears to be pro-survival rather than pro-cell death.

Effects of miR-16 plus CA19-9 detections on pancreatic cancer diagnostic performance.

BACKGROUND: Although the detection of serum carbohydrate antigen 19-9 (CA19-9) has traditionally been used for the diagonosis of pancreatic cancer, the specific markers are lacking. The miRNAs have been used as new diagnosic markers in cancer patients. The effects of miR-16 plus CA19-9 detections on pancreatic cancer diagnostic performance were analyzed in this study. METHODS AND RESULTS: 70 pancreatic cancer patients and 70 chronic pancreatitis patients were recruited from January 2011 to August 2012 and 50 healthy volunteers for comparison. Serum CA19-9 level was measured by a chemiluminescent method. Plasma miR-16 level was measured by a real-time reverse transcription-polymerase chain reaction method. The effects of detecting miR-16, CA19-9, and their combination on pancreatic cancer diagnosis were analyzed. The plasma miR-16 content of the pancreatic cancer group was higher than that of the chronic pancreatitis group (p < 0.05), but the contents of the two groups did not differ significantly. Combining miR-16 and CA19-9 detections significantly increased the sensitivity and specificity of pancreatic cancer diagnosis (LR+ > 20, LR- < 0.2). CONCLUSIONS: The combination of miR-16 and CA19-9 detections boosted the diagnostic performance in pancreatic cancer detection.

Decoy receptor 3 (DcR3) overexpression predicts the prognosis and pN2 in pancreatic head carcinoma.

BACKGROUND: This study was carried out to examine decoy receptor 3 (DcR3) expression and investigate its clinical and prognostic significance in patients with pancreatic head carcinoma. METHODS: Tissue samples were obtained from 50 patients with pancreatic head carcinoma. DcR3 protein expression in tissues and sera was assessed by immunohistochemistry and ELISA. Correlations between DcR3 and clinicopathologic features and prognoses were analyzed statistically. RESULTS: Serum DcR3 levels were significantly elevated in patients with pancreatic head carcinoma compared with patients with cystadenoma and healthy individuals (P < 0.01 and P < 0.01, respectively). DcR3 overexpression correlated with lymph node metastases and TNM stages (P < 0.05 and P < 0.05, respectively). Median overall survival for the high DcR3 group was 16.3 months, compared to 21.6 months for the low DcR3 group (P < 0.05). In the low DcR3 group, no significant difference was found in the overall survival between patients who underwent standard pancreatoduodenectomy (SPD) and those who had radical pancreatoduodenectomy (RPD) (P > 0.05). In the high DcR3 group, the median overall survival rates were 16.8 months in the RPD group and 13.5 months in the SPD group (P < 0.05). CONCLUSIONS: We found that DcR3 was overexpressed in pancreatic head carcinoma. The patients with high DcR3 levels had higher pN2 stages than those with low DcR3 levels. Detecting serum DcR3 level preoperatively might be an additional approach for evaluating pN2 stage and guiding the range of lymphadenectomy.

A Retrospective Study on the Three-Port Technique of Laparoscopic Common Bile Duct Exploration for the Management of Cholelithiasis and Choledocholithiasis.

Background: Laparoscopic cholecystectomy (LC) with laparoscopic common bile duct exploration (LCBDE) is convenient in treating cholelithiasis and choledocholithiasis due to its advantage of accelerated recovery. This retrospective study aimed to summarize the experience of cholelithiasis and choledocholithiasis treatment via three-port approach of LCBDE in Eastern China. Methods: Patients diagnosed with cholelithiasis and choledocholithiasis between July 2019 and October 2021 were included. Patients who received LC+LCBDE+primary suturing of the common bile duct (CBD) via a three-port approach were assigned to the LCBDE-P group, and those who received LC+LCBDE+T-tube drainage of CBD comprised the LCBDE-T group. The measurement data were compared between the two groups. P-values <0.05 indicated statistical significance. Results: A total of 88 patients were divided into two groups: LCBDE-P (n=50) and LCBDE-T (n=38). Multiple logistic regression analysis showed that LCBDE-P is associated with a shorter length of stay (OR=0.115, 95% CI: 0.040-0.329, P<0.001) and lower hospitalization costs (OR=0.120, 95% CI: 0.041-0.357, P<0.001). No significant differences between the two groups were detected in the operation time, intraoperative hemorrhage, clearance rate of CBD stones, postoperative liver function, and postoperative complications (P>0.05). Conclusion: The three-port approach of LCBDE is a safe and feasible strategy for managing cholelithiasis and choledocholithiasis. Compared to LCBDE-T, LCBDE-P reduces the length of hospital stay and medical costs during hospitalization.

Laparoscopic-Assisted Colorectal Resection Can Reduce the Inhibition of Immune Function Compared with Conventional Open Surgery: A Retrospective Clinical Study.

BACKGROUND: Immune function is an important indicator for assessing postoperative recovery and long-term survival in patients with malignancy, and laparoscopic surgery is thought to have a less suppressive effect on the immune response than open surgery. This study aimed to investigate this effect in a retrospective clinical study. METHODS: In this retrospective clinical study, we enrolled 63 patients with colorectal cancer in the Department of General Surgery of the First Affiliated Hospital of Soochow University and assessed the changes in their postoperative immune function by measuring CD3+T, CD4+T, CD8+T lymphocytes, and CD4+/CD8+ ratio. RESULTS: Compared with open surgery, laparoscopic colorectal surgery was effective in improving the postoperative decline in immune function. We determined that the number of CD4+, CD8+T lymphocytes, and the CD4+/CD8+ ratio was not significantly reduced in the laparoscopic group. CONCLUSION: Laparoscopic-assisted colorectal resection can reduce the inhibition of immune functions compared with conventional open surgery.

Absent in melanoma 2 attenuates proliferation and migration and promotes apoptosis of human colorectal cancer cells by activating P38MAPK signaling pathway.

Colorectal cancer (CRC) stands among the top prevalent cancers worldwide and holds a prominent position as a major contributor to cancer-related mortality globally. Absent in melanoma 2 (AIM2), a constituent of the interferon-inducible hematopoietic interferon-inducible nuclear antigens with 200 amino acid repeats protein family, contributes to both cancer progression and inflammasome activation. Despite this understanding, the precise biological functions and molecular mechanisms governed by AIM2 in CRC remain elusive. Consequently, this study endeavors to assess AIM2's expression levels, explore its potential antitumor effects, elucidate associated cancer-related processes, and decipher the underlying signaling pathways in CRC. Our findings showed a reduced AIM2 expression in most CRC cell lines. Elevation of AIM2 levels suppressed CRC cell proliferation and migration, altered cell cycle by inhibiting G1/S transition, and induced cell apoptosis. Further research uncovered the participation of P38 mitogen-activated protein kinase (P38MAPK) in AIM2-mediated modulation of CRC cell apoptosis and proliferation. Altogether, our achievements distinctly underscored AIM2's antitumor role in CRC. AIM2 overexpression inhibited proliferation and migration and induced apoptosis of CRC cells via activating P38MAPK signaling pathway, indicating AIM2 as a prospective and novel therapeutic target for CRC.

Surgical Strategies for Siewert Type II Esophagogastric Junction Carcinomas: A Randomized Controlled Trial.

Aim: To determine the ideal surgical approach for Siewert type II EGJ carcinomas. Methods: We conducted the randomized controlled trial (RCT) at Shanxi Cancer Hospital from January 2014 to August 2016. A total of 105 patients with T1-4N1-3M0 Siewert type II EGJ carcinomas were initially recruited. The final follow-up was up to June 30, 2019. Patients were randomized to undergo either a proximal gastrectomy plus jejunal interposition (PG+JI), proximal gastrectomy plus esophagogastrostomy (PG+EG), or total gastrectomy plus Roux-en-Y esophagojejunostomy (TG+RY). The primary endpoint was postoperative complications. Secondary endpoints were 5-year survival and recovery indexes. Results: Among 105 patients, 100 patients (95.2%; mean age, 56.2 years) with tumors <3cm in size underwent surgery: PG+JI (n=33) vs. PG+EG (n=33) and TG+RY (n=34); 91 patients completed the study. Among the groups, the PG+JI group had the longest reconstruction time: 34.11 ± 6.10 min vs. 21.97 ± 3.30 min (PG+EG) vs. 30.56 ± 4.26 min (TG+RY); p<0.001. There was no postoperative mortality. In the per-protocol analysis, the PG+JI group showed a decreased tendency in complication rate: 6.9% vs. 23.3% (PG+EG) vs. 18.8% (TG+RY), but there was no significant difference. For recovery indexes, the TG+RY group had the lowest values of the amount of single meal, weight loss, hemoglobin, albumin, pepsin, and gastrin among the three groups. There was no significant difference among the three groups in 5-year survival. Conclusions: Proximal gastrectomy is preferable for T1-4N1-3M0 Siewert type II EGJ carcinomas with tumors <3cm in size because of its better nutrition status under similar postoperative complication to total gastrectomy. Jejunal interposition can be recommended as a optional reconstruction approach after proximal gastrectomy. Clinical Trial Registration: https://www.chictr.org.cn/, identifier ChiCTR-IIR-16007733.

Clinical role of miR-421 as a novel biomarker in diagnosis of gastric cancer patients: A meta-analysis.

BACKGROUND: Gastric cancer (GC) has been identified as one of the most common malignancies. It was found that microRNAs can be used as potential biomarkers for GC diagnosis. The aim of this study was to estimate the diagnostic value of 4 potential microRNAs in GC. METHODS: PubMed, Embase, Cochrane Library, and Web of Science were used to search published studies. The quality of the studies was scored with the Quality Assessment of Diagnostic Accuracy Studies. The pooled sensitivity and specificity, diagnostic odds ratio (DOR) and area under the curve (AUC) were calculated. The heterogeneity was evaluated using Cochrane Q statistics and the inconsistency index. RESULTS: A total of 22 studies reporting the diagnostic value of miR-21 (n = 9), miR-106 (n = 10), miR-421 (n = 5) and miR-223 (n = 3) were included. Quality Assessment of Diagnostic Accuracy Studies scores showed the high quality of the selected 22 articles. The random effects model was adopted by evaluating the heterogeneity between articles. The DOR, AUC, and Q value of miRNA-21 were 12.37 (95% confidence interval [CI]: 5.36-28.54), 0.86 and 0.79, respectively. The DOR, AUC and Q value of miRNA-106 were 12.98 [95% CI: 7.14-23.61], 0.85 and 0.78, respectively. The DOR, AUC and Q value of miRNA-421 were 27.86 [95% CI: 6.04-128.48], 0.92 and 0.86, respectively. The DOR, AUC and Q value of miRNA-223 were 18.50 [95% CI: 7.80-43.86], 0.87 and 0.80, respectively. These results indicate that miRNA-421 has the highest diagnostic accuracy, followed by miR-223, miRNA-21, and miRNA-106 among the 4 microRNAs in GC. CONCLUSIONS: miR-21, miR-106, miR-421, and miR-223 have good diagnostic efficacy, especially miR-421, could be used as auxiliary diagnostic indicator for GC.

Pretreatment blood biomarkers combined with magnetic resonance imaging predict responses to neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

Aim: To investigate the value of pretreatment blood biomarkers combined with magnetic resonance imaging (MRI) in predicting the efficacy of neoadjuvant chemoradiotherapy (NCRT) in patients with locally advanced rectal cancer (LARC). Methods: This study involved patients with LARC who received NCRT and subsequently underwent total mesenteric excision from June 2015 to June 2021 at the First Affiliated Hospital of Soochow University. Patients with incomplete courses of neoadjuvant therapy, comorbidities with other malignancies or diseases that affect the study outcome, and those who underwent unplanned surgery were ultimately excluded. Laboratory data such as albumin, CEA, various blood cell levels, and MRI related data such as tumor regression grade assessed by magnetic resonance imaging (mrTRG) were collected from the included patients one week prior to NCRT. MrTRG is a common clinical imaging metric used to assess the degree of tumor regression in rectal cancer, primarily based on morphological assessment of residual tumor. Furthermore, pretreatment blood biomarkers such as neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), albumin to fibrinogen ratio (AFR), and prealbumin to fibrinogen ratio (PFR) were assessed. The independent variables for pathologic complete response (pCR) to NCRT were determined by univariate and multivariate logistic regression analyses. Receiver operating characteristic (ROC) curve analysis was used to examine the performance of MRI with or without pretreatment blood biomarkers in predicting pCR using DeLong's method. A nomogram was created and confirmed internally. Results: Fifty-nine individuals with LARC satisfied the inclusion criteria, among which 23 showed pCR after NCRT. Logistic regression analysis demonstrated that pretreatment CEA (≤ 3 µg/L, OR = 0.151, P = 0.039), NLR (OR = 4.205, P = 0.027), LMR (OR = 0.447, P = 0.034), and PFR (OR = 0.940, P = 0.013) were independent predictors of pCR to NCRT. The AUCs of mrTRG alone and mrTRG plus the above four pretreatment blood biomarkers were 0.721 (P =0.0003) and 0.913 (P <0.0001), respectively. The constructed nomogram showed a C-index of 0.914. Conclusion: Pretreatment blood biomarkers combined with MRI can help clinical efforts by better predicting the efficacy of NCRT in patients with locally advanced rectal cancer.

STING promotes proliferation and induces drug resistance in colorectal cancer by regulating the AMPK-mTOR pathway.

Background: In recent years, reports regarding stimulator of interferon genes (STING) and the progression of colorectal cancer (CRC) have emerged rapidly, yet their association remains controversial. This research was aimed to provide an insight into the prognostic biomarker and therapeutic target significance of STING in CRC. Methods: CRC Cell lines of HCT116 and SW480, as well as 32 paired CRC specimens were chosen for this study. STING expressions were examined by immunohistochemistry to evaluate the correlation with clinicopathological factors. Data analysis of STING expressions in colon cancer and rectal cancer were performed using The Cancer Genome Atlas (TCGA) database. siRNA was transfected into cell lines for knocking down the expression of STING. Transwell assay was employed to evaluate cell migration and invasiveness. CCK-8 assay was used for assessing the change of cell proliferation. Drug sensitive test was involved to evaluate drug resistance of cell lines. Gene Set Enrichment Analysis (GSEA) was applied for exploring potential downstream mechanism of STING in CRC progression and Western blotting is used for mechanism validation. Results: In the thirty-two paired CRC and adjacent normal tissues, we found a significant up-regulated in STING expression with immunohistochemical staining in cancer tissues compared with adjacent normal tissues (P<0.01), which was correlated with the tumor-node-metastasis (TNM) stage of patients (P=0.028). Meanwhile, GESA enrichment analysis indicated a remarkable change in mTOR signaling following STING regulation. In HCT116 and SW480 cell lines of CRC, When STING was down-regulated, its biological behavior of cell viability, cell invasion and drug sensitivity to 5-fluorouracil were significantly reduced (P<0.05), we also observed the up-regulation of P-AMPK (P<0.05) and down-regulation of p-mTOR (P<0.05). Conclusions: STING expressions was significantly up-regulated in CRC tissues. Expression of STING was correlated with the TNM stage of patients. STING is found to promote cell proliferation, invasion ability and drug resistance mediating AMPK-mTOR signaling in CRC. STING could be a promising target for the sensitization of chemotherapy and inhibits CRC progression.

TBK1 Facilitates GLUT1-Dependent Glucose Consumption by suppressing mTORC1 Signaling in Colorectal Cancer Progression.

Intestinal inflammation is a vital precipitating factor of colorectal cancer (CRC), but the underlying mechanisms are still elusive. TANK-binding kinase 1 (TBK1) is a core enzyme downstream of several inflammatory signals. Recent studies brought the impacts of TBK1 in malignant disease to the forefront, we found aberrant TBK1 expression in CRC is correlated with CRC progression. TBK1 inhibition impaired CRC cell proliferation, migration, drug resistance and tumor growth. Bioinformatic analysis and experiments in vitro showed overexpressed TBK1 inhibited mTORC1 signaling activation in CRC along with elevated GLUT1 expression without inducing GLUT1 translation. TBK1 mediated mTORC1 inhibition induces intracellular autophagy, which in turn decreasing GLUT1 degradation. As a rescue, blocking of autophagosome and retromer respectively via autophagy-related gene 7 (ATG7) or TBC1 Domain Family Member 5 (TBC1D5) silence diminished the regulation of TBK1 to GLUT1. GLUT1 staining presented that TBK1 facilitated GLUT1 membrane translocation which subsequently enhanced glucose consumption. Inhibitor of TBK1 also decreased GLUT1 expression which potentiated drug-sensitivity of CRC cell. Collectively, TBK1 facilitates glucose consumption for supporting CRC progression via initiating mTORC1 inhibition induced autophagy which decreases GLUT1 degradation and increases GLUT1 membrane location. The adaptive signaling cascade between TBK1 and GLUT1 proposes a new strategy for CRC therapy.