Identification of the microRNA alterations in extracellular vesicles derived from human haemorrhoids.

NEW FINDINGS: What is the central question of this study? What are the morphological features and microRNA (miRNA) expression features of extracellular vesicles (EVs) from haemorrhoids (Hae-EVs) and normal tissues? What are the potential functions of the differentially expressed (DE) miRNAs in Hae-EVs? What is the main finding and its importance? We present, for the first time, the morphological features and miRNA profile of human Hae-EVs. Four hundred and forty-seven significant DE-miRNAs were identified. Gene ontology and pathway analysis of the DE-miRNAs indicated diverse roles of the Hae-EVs through different pathways. Our findings provide EV-based pathological features and the underlying mechanism of haemorrhoids. ABSTRACT: Extracellular vesicles (EVs) play important roles in many pathophysiologies as cell-to-cell communication vehicles. However, the features and potential functions of the EVs in haemorrhoids remain unclear. Therefore, we performed microRNA (miRNA) microarray analysis in EVs derived from haemorrhoid tissue to identify the profile of miRNAs in these EVs and predict their potential functions. We obtained typical EVs from both haemorrhoid and control tissues. Microarray analysis identified 447 miRNAs with significant differential expresssion (DE): 245 upregulated and 202 downregulated. The top three upregulated miRNAs in haemorrhoid EVs (Hae-EVs), namely miR-6741-3p, miR-6834-3p and miR-4254, were detected by RT-qPCR in both Hae-EVs and haemorrhoid tissues. Interestingly, we found a different expression pattern in the haemorrhoid tissues from that in Hae-EVs. The potential target genes of these DE-miRNAs were predicted by the miRWalk and miRDB databases. Gene ontology (GO) analysis of the target genes showed that the DE-miRNAs contributed mainly to protein kinase activity, transcriptional activity and ubiquitin-protein function. KEGG search found that the DE-miRNAs might regulate the MAPK and Ras signalling pathways. These findings revealed, for the first time, the miRNA profiles in Hae-EVs and provided potential targets and pathways involved in the pathological process.

Blockade of the amino acid transporter SLC6A14 suppresses tumor growth in colorectal Cancer.

BACKGROUND: The amino acid transporter SLC6A14, which transports 18 of the 20 proteinogenic amino acids, is too low to be detected in healthy normal tissues but is significantly increased in some solid cancers. However, little is known about the roles of SLC6A14 in colorectal cancer (CRC). METHODS: The mRNA and protein levels of SLC6A14 were detected using TCGA database, real-time polymerase chain reaction, western blot, and tissue microarrays, respectively. Amino acids concentration was determined by LC-MS/MS. Cell proliferation and apoptosis were determined using MTT assay and flow cytometry. Transwell invasion assay and wound healing assay were employed to analyze cell migration and invasion. The protein levels of Akt-mTOR signaling pathway and MMPs proteins were detected by western blot. RESULTS: Both of the mRNA and protein levels of SLC6A14 were upregulated in CRC tissues, and the protein levels of SLC6A14 were closely related to the tumor cells differentiation: the higher the expression of SLC6A14 was, the poorer the differentiation of the tumor cells was. Further knockdown SLC6A14 with siRNA or treatment with α-MT in CRC cell lines reduced cell proliferation and migration in vitro and inhibited xenograft tumor growth in vivo. Mechanistically, SLC6A14 was demonstrated to regulate the expression and phosphorylation of Akt-mTOR, which mediates the promoting tumor growth function of SLC6A14. Blockade of SLC6A14 with α-MT inhibited the activation of mTOR signaling. CONCLUSION: SLC6A14 was upregulated in CRC and could promote tumor progression by activating the Akt-mTOR signaling pathway, which may serve as an effective molecular target for the treatment of CRC.

The clinicopathological and molecular features of sinusoidal large B-cell lymphoma.

We report 17 cases of sinusoidal large B-cell lymphoma (SLBCL). Clinical, morphologic, immunophenotypic, and molecular features were detected and analyzed. All cases showed an obvious sinusoidal growth pattern, usually associated with residual atrophic lymphoid tissue. All tumors contained large pleomorphic lymphoid cells and one or more prominent nucleoli, with abundant amphophilic cytoplasms; 15/17 cases showed anaplastic morphologic features. The patient age ranged from 43 to 80 years (median 57 years), and 7 males and 10 females were included. Eleven of 15 (73.3%) patients had Ann Arbor stage III or IV disease, and 10/15 (66.6%) patients had an International Prognostic Index (IPI) score ≥3. Immunophenotypically, 16/17 (94.1%) cases displayed a nongerminal center B-cell (non-GCB) immunophenotype. Furthermore, 16/17 (94.1%) cases were positive for CD30, and p53 was expressed in 10/16 (62.5%) cases. In total, 12/14 (85.7%) cases expressed BCL2 and MYC simultaneously (double expression), and 11/14 (78.6%) cases showed PD-L1 positivity (6/11 had a PD-L1 tumor proportion score ≥50%). Cytogenetically, concurrent MYC and BCL2 and/or BCL6 abnormalities (break-apart or extra copy) were detected in 10/15 cases, and 7/13 (53.8%) cases harbored a PD-L1/L2 amplification. TP53 mutation was found in 7/13 (53.8%) cases by Sanger sequencing. Whole-exome and large-panel sequencing results revealed high mutation frequencies of TP53 (4/7), MYD88 (3/7), KMT2D (3/7), CREBBP (3/7), and PIM1 (3/7). Among the 13 patients with SLBCL treated with aggressive chemotherapy regimens, the median overall survival (OS) was 18 months, and the 2-year OS rate was 34.6%. The OS of patients with SLBCL was markedly worse than that of 35 control group patients with common diffuse large B-cell lymphoma (DLBCL) without sinusoidal features (P < 0.001). SLBCL may represent a specific type of DLBCL that has characteristic pathologic features. The cancer is aggressive in most clinical cases, and outcomes are poor. SLBCL and anaplastic DLBCL (A-DLBCL) have many overlapping clinicopathological and molecular features.

Genetic alterations in cell cycle regulation-associated genes may promote primary progression of gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are one of the most common mesenchymal tumor types and usually contain KIT or PDGFRA mutations. GISTs with concomitant low- and high-grade components are seen in clinical practice. Herein, we retrospectively analyzed the histological characteristics and immunohistochemical results of 22 GIST cases with concomitant low- and high-grade tumors. Whole-exome sequencing (WES) was performed on ten pairs of high-grade GIST specimens and matched low-grade samples. Differential oncogenes mutated only in high-grade GISTs were identified, which were confirmed by Sanger sequencing. Fluorescence in situ hybridization was employed to detect MYC copy number variation. High-grade GISTs were more likely to have lower CD34 expression and a higher Ki-67 proliferation index compared to the matched low-grade tumors. WES identified 30 differential cancer-associated genes mutated only in high-grade GISTs; Sanger sequencing confirmed ten relevant differential oncogenic mutations in nine genes (MGA, ARID1A, LATS2, MAX, PIK3CA, RB1, RPS6KB2, SDHA, and SETD2). Two patients had MGA mutations, whereas other gene mutations occurred in only one patient. Most of the differential cancer-associated genes are mainly involved in cell cycle control. MYC copy number gain was a common genetic variation. High-grade GISTs revealed more MYC copy number gains than matched low-grade tumors, and low-grade GISTs with coexisting high-grade components showed more MYC copy number gains than pure low-grade GISTs. Moreover, MYC copy number gain was positively correlated with the mitotic index and Ki-67 proliferation index. Alterations in cell cycle regulation-associated genes, such as genetic mutations and MYC copy number gain, may promote primary progression from low-grade GISTs to high-grade tumors by regulating tumor cell proliferation.

Transrectal Natural Orifice Specimen Extraction (NOSE) With Oncological Safety: A Prospective and Randomized Trial.

BACKGROUND: In the present paper, we introduce our experience with the novel method during laparoscopic anterior resection of upper rectal or sigmoid colon cancer by transrectal natural orifice specimen extraction (NOSE). METHODS: A prospective randomized controlled trial was performed from June 2016 to May 2019. Patients with upper rectal or sigmoid colon cancer were randomized in a 1:1 ratio to the NOSE group and the non-NOSE group. Preoperative and postoperative clinical variables were analyzed and compared between groups. Postoperative pain was analyzed utilizing a visual analog scale. Postoperative overall survival was analyzed using a Kaplan-Meier curve. RESULTS: A total of 276 patients were enrolled, of whom 254 were randomly divided into the NOSE group (n = 122) and the conventional laparoscopic group (n = 119). NOSE failed in 22 cases, which were converted to transabdominal specimen extraction. Intention-to-treat analysis was performed, and these 22 cases were included in the NOSE group. The incidence of postoperative complications was significantly lower in the NOSE group (11/122, 9%) than in the non-NOSE group (25/119, 21%). The NOSE group had a longer operation time, less blood loss, and a lower postoperative visual analog scale score than the non-NOSE group. The time for intestinal function recovery (ventilation) and the length of hospital stay were significantly longer in the non-NOSE group. The Kaplan-Meier survival curve showed no statistically significant difference in the disease-free survival rate between the NOSE group and the non-NOSE group. CONCLUSIONS: The novel NOSE method is safe and feasible to use in patients having colorectal cancer. Compared with traditional laparoscopic surgery, the postoperative complication rates of NOSE surgery were lower with an improved short-term clinical recovery.

YY1 mediates TGF-ß1-induced EMT and pro-fibrogenesis in alveolar epithelial cells.

Pulmonary fibrosis is a chronic, progressive lung disease associated with lung damage and scarring. The pathological mechanism causing pulmonary fibrosis remains unknown. Emerging evidence suggests prominent roles of epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AECs) in myofibroblast formation and progressive pulmonary fibrosis. Our previous work has demonstrated the regulation of YY1 in idiopathic pulmonary fibrosis and pathogenesis of fibroid lung. However, the specific function of YY1 in AECs during the pathogenesis of pulmonary fibrosis is yet to be determined. Herein, we found the higher level of YY1 in primary fibroblasts than that in primary epithelial cells from the lung of mouse. A549 and BEAS-2B cells, serving as models for type II alveolar pulmonary epithelium in vitro, were used to determine the function of YY1 during EMT of AECs. TGF-ß-induced activation of the pro-fibrotic program was applied to determine the role YY1 may play in pro-fibrogenesis of type II alveolar epithelial cells. Upregulation of YY1 was associated with EMT and pro-fibrotic phenotype induced by TGF-ß treatment. Targeted knockdown of YY1 abrogated the EMT induction by TGF-ß treatment. Enforced expression of YY1 can partly mimic the TGF-ß-induced pro-fibrotic change in either A549 cell line or primary alveolar epithelial cells, indicating the induction of YY1 expression may mediate the TGF-ß-induced EMT and pro-fibrosis. In addition, the translocation of NF-κB p65 from the cytoplasm to the nucleus was demonstrated in A549 cells after TGF-ß treatment and/or YY1 overexpression, suggesting that NF-κB-YY1 signaling pathway regulates pulmonary fibrotic progression in lung epithelial cells. These findings will shed light on the better understanding of mechanisms regulating pro-fibrogenesis in AECs and pathogenesis of lung fibrosis.

TCEA3 Attenuates Gastric Cancer Growth by Apoptosis Induction.

BACKGROUND: The aim of this study was to investigate and interpret the expression level and potential function of TCEA3 in gastric cancer. MATERIAL AND METHODS: qRT-PCR was used to determine the expression level of TCEA3 in gastric cancer tissues. Pearson χ2 test was performed to clarify the correlation between TCEA3 expression and patients' clinicopathologic characteristics. Biological function of TCEA3 was tested by proliferation assay and colony formation assay. Flow cytometry was used to study the potential function of TCEA3 in apoptosis induction. RESULTS: TCEA3 expression was significantly downregulated in gastric cancer tissues compared with paired normal tissues. Poor prognoses were observed in the low TCEA3 expression group of patients in contrast to the high TCEA3 expression group. Functionally, upregulation of TCEA3 inhibited gastric cancer cell proliferation and colony formation. We also found that TCEA3 may attenuate cell growth through apoptosis induction. CONCLUSIONS: Our findings suggest that TCEA3 attenuates the proliferation and induces apoptosis of gastric cancer cells.

Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes.

Acquired resistance to chemotherapeutic drugs in gallbladder cancer (GBC) results in therapy failure. This study is aimed to establish oxaliplatin (OXA)-resistant GBC cell lines and uncover their gene expression profiles. First, two OXA-resistant GBC cell lines (GBC-SD/OXA and SGC996/OXA) were established by gradually increasing the drug concentration, and the resistance index was 4-5. The two resistant cell lines showed slower proliferation and higher stemness, colony formation, and migration abilities. Epithelial mesenchymal transformation and increased levels of P-glycoprotein were also detected. Next RNA-sequence analysis identified 4,675 dysregulated genes (DGs) in resistant cells, and most of the 12 randomly selected DGs were verified to be consistent with the sequence results. Kyoto Encyclopedia of Genes and Genomes analysis indicated that several DGs were involved in resistance- and phenotype-related pathways, of which the activations of PD-L1 and ERK1/2 were both verified in resistant cell lines. In conclusion, this study is the first to report the gene expression profile of OXA-resistant GBC cells and provides a useful database for target development.

The change in nutritional status is related to cardiovascular events in patients with pacemaker implantation: A 4-year follow-up study.

Background: The aim of our study was to evaluate changes in nutritional status as measured by the prognostic nutritional index (PNI) and geriatric nutritional risk index (GNRI) scores, and their abilities to predict clinical prognosis in patients with pacemaker implantation (PMI). Methods: A total of 595 patients who underwent permanent PMI from January 2011 to December 2020 were included. PNI and GNRI scores were separately calculated at the beginning day of PMI operation and at the end of 12-month follow-up, and their net changes (Δ) were calculated by PNI or GNRI scores at follow-up minus the corresponding scores on admission. The cohort patients were divided into low risk of malnutritional status (ΔPNI or ΔGNRI scores ≥ 0) and high risk of malnutritional status (ΔPNI or ΔGNRI scores < 0) groups. Primary outcome measure was a composite major adverse cardiovascular event (MCE), defined as heart failure hospitalization (HFH), myocardial infarction (MI), stroke, or death from any cause, presented as hazard ratios (HR) with 95% confidence intervals (CI) calculated by MCE in the crude or multivariate-adjusted Cox Proportional Hazards models. Receiver operating characteristic (ROC) curve analysis was used to compare the differential ability to predict incident MCEs betweenΔPNI andΔGNRI scores. Results: In total, 16% of patients developed the MCE during the follow-up. The cumulative event rates determined by Kaplan-Meier analysis were significantly higher in the high risk of malnutritional patients compared to the low risk of malnutritional patients (P < 0.05). Adjusted multivariate analysis showed that decreased PNI scores (HR: 2.228, 95% CI: 1.482-3.350) and decreased GNRI scores (HR: 2.178, 95% CI: 1.439-3.295) were independently associated with favorable outcomes. ROC curve analysis revealed an area under curve (AUC) of 0.586 forΔPNI scores and AUC of 0.592 for ΔGNRI scores, but their predictive abilities were not statistically different. Conclusion: Either positive change of PNI or GNRI scores were associated with reduced risk of MCEs in patients with PMI, and they have similar ability to predict clinical cardiometabolic risk. Additional enhancing nutritional status during follow-up may help to prevent unfavorable prognosis in clinical practices.

Prognostic Nutritional Index and Major Cardiovascular Events in Patients Undergoing Invasive Coronary Angiography: A Clinical Retrospective Study.

We aimed to examine whether prognostic nutritional index (PNI) could serve as an auxiliary predictor for major cardiovascular events (MCEs) in patients undergoing invasive coronary angiography (ICA). A total of 485 participants were enrolled, divided into low-PNI (≥47.40) and high-PNI (<47.40) groups. ICA determined the stenotic vessels of coronary artery disease. The primary outcome was incidental MCEs, a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or rehospitalization of in-stent restenosis. There were 47 (9.69%) MCEs during the 3.78-years follow-up. The cumulative incidence of MCEs was significantly higher in the low-PNI patients compared with the high-PNI patients (17.07% vs. 7.18%, p = 0.001). Malnutrition risk (low PNI) was significantly and independently associated with a higher risk of MCEs (hazard ratios: 2.593, 95% confidence intervals [CI]: 1.418−4.742). Combined use of the number of stenotic vessels with malnutrition risk showed a higher capacity to predict the MCEs than the presence of stenotic vessels alone (areas under the receiver operator characteristic curve: 0.696 [95% CI, 0.618−0.775] vs. 0.550 [95% CI, 0.466−0.633], p = 0.013). In conclusion, lower PNI levels may predict a higher risk of cardiovascular events in patients undergoing ICA, which supports the necessity of the risk assessment of nutrition status and guide the clinical treatment on strengthening nutritional support before ICA is performed, as well as nutritional intervention after ICA.

Phosphorylation of PBK/TOPK Tyr74 by JAK2 promotes Burkitt lymphoma tumor growth.

Burkitt lymphoma (BL), which is characterized by high invasiveness, is a subgroup of non-Hodgkin lymphoma. Although BL is regarded as a highly curable disease, especially for children, some patients unfortunately still do not respond adequately. The understanding of the etiology and molecular mechanisms of BL is still limited, and targeted therapies are still lacking. Here, we found that T-LAK cell-derived protein kinase (TOPK) and phosphorylated Janus kinase 2 (p-JAK2) are highly expressed in the tissues of BL patients. We report that TOPK directly binds to and is phosphorylated at Tyr74 by JAK2. Histone H3, one of the downstream targets of TOPK, is also phosphorylated in vivo and in vitro. Furthermore, we report that the phosphorylation of TOPK at Tyr74 by JAK2 plays a vital role in the proliferation of BL cells and promotes BL tumorigenesis in vivo. Phosphorylation of TOPK at Tyr74 by JAK2 enhances the stability of TOPK. Collectively, our results suggest that the JAK2/TOPK/histone H3 axis plays a key role in the proliferation of BL cells and BL tumorigenesis in vivo.

Overexpression of OTX1 promotes tumorigenesis in patients with esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a multifactorial disease and the sixth leading cause of death from cancer worldwide. Patients with ESCC usually have a short survival period due to the late stage at diagnosis. Incidence rates of ESCC remain high among the elderly. With recent advances, it has been demonstrated that ESCC tumors display a unique genetic profile. This study aimed to examine the possible function of OTX1 in ESCC. METHODS: We collected paraffin-embedded tumor tissues from 107 patients originally diagnosed with ESCC at Xijing Hospital and fresh-harvested and paired adjacent normal esophageal tissues from 15 ESCC patients undergoing curative resection. The expression level of OTX1 was evaluated through immunohistochemistry and western blot. Prognostic and survival analyses were conducted using univariate/multivariate analysis and log-rank analysis with SPSS 23.0. Cell models and xenograft models were used to examine the overexpression of OTX1 in vivo and in vitro. RESULTS: OTX1 was overexpressed in ESCC tissues compared with normal esophageal tissues. Both the mRNA expression level and protein level of OTX1 were higher than they were in paired normal tissue. Prognostic and OS analyses showed that the OTX1 expression level was an individual prognostic factor in ESCC patients. Cell viability was significantly promoted when OTX1 was overexpressed in ESCC cell, Furthermore, downregulating OTX1 in EC109 cell significantly attenuated the cell proliferation migration and invasion. Flow cytometric detection showed that cells overexpressing OTX1 were predominantly in the S and G2&M phases. In the xenograft model, both tumor size and weight in the OTX1 overexpression group were significantly larger than those in the control group. CONCLUSION: OTX1 is an independent prognostic factor of ESCC and contributes to tumorigenesis both in vivo and in vitro.

TRIM22 inhibits the proliferation of gastric cancer cells through the Smad2 protein.

TRIM22 is involved in tumorigenesis and development, but its mechanism is not clear. In this study, we investigated the expression and biological role of TRIM22 in gastric cancer. We found that TRIM22 mRNA and protein expression was abnormally low in gastric cancer tissues and cells and correlated with tumor size and depth of invasion. Overexpression of TRIM22 significantly inhibited the proliferation, colony formation, and migration of gastric cancer cells and downregulated the expression of HSPA6. However, the HSPA6-siRNA complementation test showed that TRIM22 did not regulate cell proliferation through HSPA6. Furthermore, overexpression of TRIM22 downregulated the phosphorylation of Smad2 and Smad3. In addition, TRIM22 directly binds to Smad2, and overexpression of Smad2 can reverse the inhibition of cell proliferation and migration induced by TRIM22. In vivo, overexpression of TRIM22 significantly inhibited the growth of subcutaneous xenografts in nude mice. Our study indicates that TRIM22 has an important role in the development of gastric cancer and may inhibit the proliferation of gastric cancer cells through Smad2.

REG4 is a Potential Biomarker for Radiochemotherapy Sensitivity in Colorectal Cancer.

PURPOSE: Colorectal cancer (CRC) is one of the most common types of malignancies, and radiochemotherapy (RCT) followed by surgery is the recommended approach for CRC treatment. However, some cases do not respond to first-line conventional chemotherapy or even progress further after treatment. Moreover, there is a risk of severe side effects, such as radiodermatitis. Therefore, identifying predictors for RCT sensitivity is an essential step toward predicting and eventually overcoming resistance. MATERIALS AND METHODS: We used integrative bioinformatics analysis and experimental validation to show that regenerating family member 4 (REG4) may be a potential biomarker for RCT sensitivity in CRC. RESULTS: REG4, whose expression is upregulated in some CRC tissues and downregulated in RCT-sensitive CRC cells, was identified as a potential genetic marker for RCT sensitivity in CRC. Immunohistochemistry-based tissue microarray of human CRC was used to experimentally validate REG4 data obtained from the bioinformatics analysis. CONCLUSION: Collectively, these results indicate that REG4 may be a potential biomarker for RCT sensitivity in CRC.

High RSK4 expression constitutes a predictor of poor prognosis for patients with clear cell renal carcinoma.

BACKGROUND: This research focuses on exploring RSK4 protein expression within Clear Cell Renal Cell Carcinoma (ccRCC), based on these investigations on level of expressions coupled with the relevance to clinicopathologic features and clinical outcomes. METHODS: The expression of RSK4 in 48 ccRCC and 20 hydronephrosis samples were under the detection of immunohistochemistry; besides, its relevance to the combination of clinicopathologic features with prognosis was committed in virtue of statistical approaches. RESULTS: The 48 ccRCC samples included 36 (75%, 36/48) positive for RSK4, while the positive rate in hydronephrosis samples were 5 (25%, 5/20). Statistical analysis showed that RSK4 in ccRCC samples express higher expression the hydronephrosis samples (P < 0.05). Furthermore, the expression of RSK4 in ccRCC samples weren't correlated with ages and genders (P > 0.05), while WHO/ISUP nucleolar grade harboured relevance to low survival rate (P = 0.018). Molecular researches demonstrated that over-expression of RSK4 was able to upgrade the proliferation capability of ccRCC cell lines. CONCLUSIONS: According to the expression pattern and molecular systems featured RSK4 in ccRCCs, it performed the function of a latent independent prognostic factor performing the function of a newly built latent therapeutic aim oriented with the patients undergoing RCC. Moreover, the specific mechanism of action is expected to be revealed in the future research.

Restoring HOXD10 Exhibits Therapeutic Potential for Ameliorating Malignant Progression and 5-Fluorouracil Resistance in Colorectal Cancer.

Emerging evidence suggests that hypermethylation of HOXD10 plays an important role in human cancers. However, the biological and clinical impacts of HOXD10 overmethylation and its downstream targets in colorectal cancer remain unknown. We evaluated the methylation level of HOXD10 in paired cancer and normal tissues (n = 42) by using pyrosequencing, followed by validation of the methylation status of HOXD10 from The Cancer Genome Atlas (TCGA) datasets with 302 cancer tissues and 38 normal tissues. The biological function of HOXD10 was characterized in cell lines. We further evaluated the effects of HOXD10 and its targets on chemoresistance in our established resistant cell lines and clinical cohort (n = 66). HOXD10 was found frequently methylated in colorectal cancer, and its hypermethylation correlates with its low expression level, advanced disease, and lymph node metastasis. Functionally, HOXD10 acts as a tumor suppressor gene, in which HOXD10-expressing cells showed suppressed cell proliferation, colony formation ability, and migration and invasion capacity. Mechanistically, DNMT1, DNMT3B, and MeCP2 were recruited in the HOXD10 promoter, and demethylation by 5-Aza-2'-deoxycytidine (5-Aza-CdR) treatment or MeCP2 knockdown can sufficiently induce HOXD10 expression. HOXD10 regulates the expressions of miR-7 and IGFBP3 in a promoter-dependent manner. Restoration of the expression of HOXD10 in 5-fluorouracil (5-FU)-resistant cells significantly upregulates the expressions of miR-7 and IGFBP3 and enhances chemosensitivity to 5-FU. In conclusion, we provide novel evidence that HOXD10 is frequently methylated, silenced, and contributes to the development of colorectal cancers. Restoration of HOXD10 activates the expressions of miR-7 and IGFBP3 and results in an inhibited phenotype biologically, suggesting its potential therapeutic relevance in colorectal cancer (CRC).

LINC00941 promotes glycolysis in pancreatic cancer by modulating the Hippo pathway.

Pancreatic ductal adenocarcinoma (PDAC) is one of most lethal cancers and is projected to be the second leading cause of cancer deaths in the United States by 2030. The lack of effective treatment and increased incidence in PDAC encourage a deeper knowledge of PDAC progression. By analyzing a long noncoding RNA (lncRNA) dataset, we found that increased LINC00941 expression led to poor outcomes in PDAC patients. Furthermore, in vitro and in vivo experiments revealed that LINC00941 promoted PDAC cancer cell growth by enhancing aerobic glycolysis. Mechanistically, LINC00941 was found to interact with mammalian STE20-like protein kinase 1 (MST1), which facilitated the protein phosphatase 2A (PP2A)-mediated dephosphorylation of MST1, resulting in Hippo pathway activation and consequently, enhanced glycolysis in PDAC. These results suggest that LINC00941 plays a key role in regulating PDAC tumorigenesis, potentially highlighting novel avenues for PDAC therapy.

Prominent roles of ribosomal S6 kinase 4 (RSK4) in cancer.

RSK4 refers to one Ser/Thr protein kinase functioning downstream pertaining to the signaling channel of protein kinase (MAPK) stimulated by Ras/mitogen. RSK4 can regulate numerous substrates impacting cells' surviving state, growing processes and proliferating process. Thus, dysregulated RSK4 active state display a relationship to several carcinoma categories, covering breast carcinoma, esophageal squamous cell carcinoma, glioma, colorectal carcinoma, lung carcinoma, ovarian carcinoma, leukemia, endometrial carcinoma, and kidney carcinoma. Whether RSK4 is a tumor suppressor gene or one oncogene remains controversial. No specific inhibiting elements for RSK4 have been found. This review briefs the existing information regarding RSK4 activating process, the function and mechanism of RSK4 in different tumors, and the research progress and limitations of existing RSK inhibitors. RSK4 may be a potential target of molecular therapy medicine in the future.

Factors influencing the application of transrectal natural orifice specimen extraction performed laparoscopically for colorectal cancer: A retrospective study.

BACKGROUND: A few factors influence the feasibility of transrectal natural orifice specimen extraction (NOSE) surgery for colorectal cancers. However, little is known about the underlying factors of NOSE surgery. METHODS: Consecutive patients with rectal and sigmoid colon cancers treated laparoscopically between January 2014 and April 2017 were enrolled in this study. The transrectal NOSE performed laparoscopically was the first choice of all patients. When NOSE failed, the specimen was removed through a midline abdominal wall incision. Univariate and multivariate logistic regression analyses were performed to identify challenging factors influencing the intraoperative specimen extraction. RESULTS: Overall, 412 consecutive patients were included. NOSE performed laparoscopically was successful in 278 patients (75.5%) and unsuccessful in 90 patients (24.5%). The multivariate analyses indicated that body mass index (BMI; odds ratio [OR] = 3.510, 95% confidence interval [CI]: 1.333-9.243, p = 0.011), mesenteric thickness (OR = 1.069, 95% CI: 1.032-1.107, p < 0.001), maximum tumor diameter (OR = 2.827, 95% CI: 1.094-7.302, p = 0.032), and tumor T stage (OR = 2.831, 95% CI: 1.258-6.369, p = 0.012) were the factors influencing the feasibility of NOSE surgery. CONCLUSION: A successful transrectal NOSE surgery was associated with a lower BMI, thinner mesentery, lesser tumor diameter, and earlier tumor T stage.

Decreased infiltration of CD4+ Th1 cells indicates a good response to ursodeoxycholic acid (UDCA) in primary biliary cholangitis.

BACKGROUND: Primary biliary cholangitis (PBC) is characterized by nonsuppurative destructive cholangitis and is thought to be an autoimmune disorder. Currently, ursodeoxycholic acid (UDCA) is the only FDA approved first-line therapy for PBC, but up to nearly one-third of patients do not achieve a complete response to this treatment. Adaptive immune cells, including T cells and B cells, have been found in the portal tracts and the bile duct epithelium and play a role in the pathogenesis of PBC, but the importance of these cells for evaluating the therapeutic response to UDCA in PBC has not yet been studied. METHODS: In this study, we collected liver puncture biopsy specimens from 34 matched patients with PBC before and after UDCA treatment and investigated the relationship between the infiltration of adaptive immune cells and the treatment response to UDCA. The extent of immune cell infiltration was determined by immunohistochemical analysis. Responses were defined based on Paris-I criteria. RESULTS: After 1 year of treatment, 25/34 patients responded to UDCA treatment according to Paris-I criteria (responders), and 9/34 patients were nonresponders. Immunohistochemical analysis showed that UDCA responders exhibited significantly less CD4+ T cell infiltration after UDCA treatment than before (50.4 ± 7.5/HPF vs 30.0 ± 7.9/HPF, P = 0.002). In contrast, UDCA nonresponders exhibited significantly more CD4+ T cell infiltration after UDCA treatment than before (32.2 ± 8.0/HPF vs 75.0 ± 13.9/HPF, P = 0.045). Moreover, patients who exhibited a reduction in CD4+ T cell infiltration after UDCA treatment had a higher response rate than those that exhibited an increase in CD4+ T cell infiltration (85.7 % vs 53.8 %, P = 0.041). However, CD3+ T cell, CD8+ T cell, and CD20+ B cell infiltration was not significantly different before and after treatment in either UDCA responders or nonresponders. Furthermore, we found that the number of infiltrating T-bet+ Th1 cells was much lower after UDCA treatment than before in responders (10.5 ± 5.7/HPF vs. 5.16 ± 4.0/HPF, P = 0.0214) but much higher in nonresponders after treatment than before (1.89±1.2/HPF vs. 12.3±5.4/HPF, P = 0.043). However, there was no difference in the extent of GATA3+ Th2 or FOXP3+ Treg infiltration before and after treatment in either UDCA responders or nonresponders. CONCLUSION: Collectively, our results suggest that a decrease in the number of liver-infiltrating CD4+ Th1 cells is associated with a good response of PBC patients to UDCA treatment. Immunohistochemical analysis of CD4 and T-bet in PBC liver specimens may be a potential approach for evaluating the therapeutic response to UDCA.