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1.
Dev Cell ; 59(9): 1175-1191.e7, 2024 May 06.
Article in English | MEDLINE | ID: mdl-38521055

ABSTRACT

In pyloric metaplasia, mature gastric chief cells reprogram via an evolutionarily conserved process termed paligenosis to re-enter the cell cycle and become spasmolytic polypeptide-expressing metaplasia (SPEM) cells. Here, we use single-cell RNA sequencing (scRNA-seq) following injury to the murine stomach to analyze mechanisms governing paligenosis at high resolution. Injury causes induced reactive oxygen species (ROS) with coordinated changes in mitochondrial activity and cellular metabolism, requiring the transcriptional mitochondrial regulator Ppargc1a (Pgc1α) and ROS regulator Nf2el2 (Nrf2). Loss of the ROS and mitochondrial control in Ppargc1a-/- mice causes the death of paligenotic cells through ferroptosis. Blocking the cystine transporter SLC7A11(xCT), which is critical in lipid radical detoxification through glutathione peroxidase 4 (GPX4), also increases ferroptosis. Finally, we show that PGC1α-mediated ROS and mitochondrial changes also underlie the paligenosis of pancreatic acinar cells. Altogether, the results detail how metabolic and mitochondrial changes are necessary for injury response, regeneration, and metaplasia in the stomach.


Subject(s)
Amino Acid Transport System y+ , Ferroptosis , Metaplasia , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Reactive Oxygen Species , Regeneration , Stomach , Animals , Reactive Oxygen Species/metabolism , Mice , Ferroptosis/physiology , Stomach/pathology , Regeneration/physiology , Amino Acid Transport System y+/metabolism , Amino Acid Transport System y+/genetics , Metaplasia/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Mitochondria/metabolism , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , Gastric Mucosa/metabolism , Mice, Inbred C57BL , Chief Cells, Gastric/metabolism , Acinar Cells/metabolism , Mice, Knockout , Phospholipid Hydroperoxide Glutathione Peroxidase , Intercellular Signaling Peptides and Proteins
2.
J Gastroenterol ; 59(4): 285-301, 2024 04.
Article in English | MEDLINE | ID: mdl-38242996

ABSTRACT

Most gastric cancers arise in the setting of chronic inflammation which alters gland organization, such that acid-pumping parietal cells are lost, and remaining cells undergo metaplastic change in differentiation patterns. From a basic science perspective, recent progress has been made in understanding how atrophy and initial pyloric metaplasia occur. However, pathologists and cancer biologists have long been focused on the development of intestinal metaplasia patterns in this setting. Arguably, much less progress has been made in understanding the mechanisms that lead to the intestinalization seen in chronic atrophic gastritis and pyloric metaplasia. One plausible explanation for this disparity lies in the notable absence of reliable and reproducible small animal models within the field, which would facilitate the investigation of the mechanisms underlying the development of gastric intestinal metaplasia (GIM). This review offers an in-depth exploration of the current state of research in GIM, shedding light on its pivotal role in tumorigenesis. We delve into the histological subtypes of GIM and explore their respective associations with tumor formation. We present the current repertoire of biomarkers utilized to delineate the origins and progression of GIM and provide a comprehensive survey of the available, albeit limited, mouse lines employed for modeling GIM and engage in a discussion regarding potential cell lineages that serve as the origins of GIM. Finally, we expound upon the myriad signaling pathways recognized for their activity in GIM and posit on their potential overlap and interactions that contribute to the ultimate manifestation of the disease phenotype. Through our exhaustive review of the progression from gastric disease to GIM, we aim to establish the groundwork for future research endeavors dedicated to elucidating the etiology of GIM and developing strategies for its prevention and treatment, considering its potential precancerous nature.


Subject(s)
Gastritis, Atrophic , Precancerous Conditions , Stomach Neoplasms , Animals , Mice , Stomach Neoplasms/genetics , Precancerous Conditions/pathology , Biomarkers , Metaplasia , Gastric Mucosa/pathology
3.
Nat Commun ; 14(1): 822, 2023 02 14.
Article in English | MEDLINE | ID: mdl-36788228

ABSTRACT

Peritoneal metastasis is the leading cause of death for gastrointestinal cancers. The native and therapy-induced ascites ecosystems are not fully understood. Here, we characterize single-cell transcriptomes of 191,987 ascites cancer/immune cells from 35 patients with/without gastric cancer peritoneal metastasis (GCPM). During GCPM progression, an increase is seen of monocyte-like dendritic cells (DCs) that are pro-angiogenic with reduced antigen-presenting capacity and correlate with poor gastric cancer (GC) prognosis. We also describe the evolution of monocyte-like DCs and regulatory and proliferative T cells following therapy. Moreover, we track GC evolution, identifying high-plasticity GC clusters that exhibit a propensity to shift to a high-proliferative phenotype. Transitions occur via the recently described, autophagy-dependent plasticity program, paligenosis. Two autophagy-related genes (MARCKS and TXNIP) mark high-plasticity GC with poorer prognosis, and autophagy inhibitors induce apoptosis in patient-derived organoids. Our findings provide insights into the developmental trajectories of cancer/immune cells underlying GCPM progression and therapy resistance.


Subject(s)
Peritoneal Neoplasms , Stomach Neoplasms , Humans , Ascites/genetics , Peritoneal Neoplasms/genetics , Peritoneal Neoplasms/secondary , Peritoneum/pathology , Stomach Neoplasms/pathology
4.
Mil Med Res ; 9(1): 15, 2022 04 07.
Article in English | MEDLINE | ID: mdl-35387671

ABSTRACT

BACKGROUND: Currently, there is no formal consensus regarding a standard classification for gastric cancer (GC) patients with < 16 retrieved lymph nodes (rLNs). Here, this study aimed to validate a practical lymph node (LN) staging strategy to homogenize the nodal classification of GC cohorts comprising of both < 16 (Limited set) and ≥ 16 (Adequate set) rLNs. METHODS: All patients in this study underwent R0 gastrectomy. The overall survival (OS) difference between the Limited and Adequate set from a large Chinese multicenter dataset was analyzed. Using the 8th American Joint Committee on Cancer (AJCC) pathological nodal classification (pN) for GC as base, a modified nodal classification (N') resembling similar analogy as the 8th AJCC pN classification was developed. The performance of the proposed and 8th AJCC GC subgroups was compared and validated using the Surveillance, Epidemiology, and End Results (SEER) dataset comprising of 10,208 multi-ethnic GC cases. RESULTS: Significant difference in OS between the Limited and Adequate set (corresponding N0-N3a) using the 8th AJCC system was observed but the OS of N0limited vs. N1adequate, N1limited vs. N2adequate, N2limited vs. N3aadequate, and N3alimited vs. N3badequate subgroups was almost similar in the Chinese dataset. Therefore, we formulated an N' classification whereby only the nodal subgroups of the Limited set, except for pT1N0M0 cases as they underwent less extensive surgeries (D1 or D1 + gastrectomy), were re-classified to one higher nodal subgroup, while those of the Adequate set remained unchanged (N'0 = N0adequate + pT1N0M0limited, N'1 = N1adequate + N0limited (excluding pT1N0M0limited), N'2 = N2adequate + N1limited, N'3a = N3aadequate + N2limited, and N'3b = N3badequate + N3alimited). This N' classification demonstrated less heterogeneity in OS between the Limited and Adequate subgroups. Further analyses demonstrated superior statistical performance of the pTN'M system over the 8th AJCC edition and was successfully validated using the SEER dataset. CONCLUSION: The proposed nodal staging strategy was successfully validated in large multi-ethnic GC datasets and represents a practical approach for homogenizing the classification of GC cohorts comprising of patients with < 16 and ≥ 16 rLNs.


Subject(s)
Stomach Neoplasms , Gastrectomy , Humans , Lymph Nodes/pathology , Lymph Nodes/surgery , Neoplasm Staging , Prognosis , Stomach Neoplasms/surgery
5.
Oncol Rep ; 47(4)2022 Apr.
Article in English | MEDLINE | ID: mdl-35169861

ABSTRACT

Following the publication of the above paper, an interested reader drew to the authors' attention that, in Fig. 5D, the data panels selected to represent the 'SKOV3 with miR­148a mimics' and 'SKOV3 with Negative Control' experiments appeared to contain overlapping data, such that they may have been derived from the same original source. The authors have re­examined their original data, and realized how the errors in the compilation of Fig. 5 arose. The corrected version of Fig. 5, showing the correct data for the 'SKOV3 with miR­148a mimics' panel in Fig. 5D and the 'SKOV3 with Negative Control' panel in Fig. 5C, is shown on the next page. Note that these errors did not affect the overall conclusions reported in the study. The authors are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish this Corrigendum; furthermore, they apologize for any inconvenience caused to the readership of the Journal. [the original article was published in Oncology Reports 27: 447-454, 2012; DOI: 10.3892/or.2011.1482].

6.
Ann Surg Oncol ; 29(6): 3684-3693, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35181815

ABSTRACT

BACKGROUND: Brain metastases (BMs) are the most serious complication of lung cancer, affecting the prognosis of lung cancer patients, and pose distinct clinical challenges. This study was designed to explore the prognostic factors related to lung cancer BM and the value of surgical resection in BMs from lung cancer. METHODS: A retrospective analysis was performed on 714 patients with lung cancer BMs screened between January 2010 and January 2018 at the Sun Yat-sen University Cancer Center. A 1:1 propensity score matching analysis was performed to reduce the potential bias between the surgery and the nonsurgery group. In both the raw and the propensity-score matched dataset, univariate and multivariate Cox proportional hazards regression analyses were used to evaluate risk factors for survival. RESULTS: After matching, 258 patients (129 surgery, 129 no surgery) were analyzed. Multivariate analyses after propensity score matching demonstrated that surgical resection was an independent protective factor for overall survival (OS), and older age, lower Karnofsky Performance Scale (KPS) score, and extracranial metastases were independent risk factors for worse OS. Patients without extracranial metastases, without synchronous BM and with a single BM had a better prognosis. CONCLUSIONS: The findings showed that surgical resection, age, KPS score, and extracranial metastases are independent prognostic factors for predicting the OS of patients with lung cancer BMs, and surgical resection for brain metastatic lesions could significantly improve the OS. However, only certain groups of patients with BMs can benefit from intracranial lesion resection, such as no extracranial metastases and metachronous metastases.


Subject(s)
Brain Neoplasms , Lung Neoplasms , Brain Neoplasms/secondary , Cohort Studies , Humans , Lung Neoplasms/pathology , Prognosis , Retrospective Studies
7.
Cell Mol Gastroenterol Hepatol ; 13(1): 19-33, 2022.
Article in English | MEDLINE | ID: mdl-34547535

ABSTRACT

The stomach is a complex and physiologically necessary organ, yet large differences in physiology between mouse and human stomachs have impeded translation of physiological discoveries and drug screens performed using murine gastric tissues. Gastric cancer (GC) is a global health threat, with a high mortality rate and limited treatment options. The heterogeneous nature of GC makes it poorly suited for current "one size fits all" standard treatments. In this review, we discuss the rapidly evolving field of gastric organoids, with a focus on studies expanding cultures from primary human tissues and describing the benefits of mouse organoid models. We introduce the differing methods for culturing healthy gastric tissue from adult tissues or pluripotent stem cells, discuss the promise these systems have for preclinical drug screens, and highlight applications of organoids for precision medicine. Finally, we discuss the limitations of these models and look to the future to present potential ways gastric organoids will advance treatment options for patients with GC.


Subject(s)
Organoids , Stomach Neoplasms , Animals , Disease Models, Animal , Humans , Mice , Precision Medicine
8.
BMC Cancer ; 21(1): 1214, 2021 Nov 13.
Article in English | MEDLINE | ID: mdl-34773999

ABSTRACT

BACKGROUND: Neoadjuvant therapy can lead to different tumor regression grades (TRG) in rectal cancer after neoadjuvant therapy. The purposes of this study are to investigate the relationships among TRG, pathologic complete response (pCR) and long-term survival, on the basis of reconstructed individual patient data (IPD). METHODS: The PubMed, Embase, Ovid and Cochrane CENTRAL databases were searched. The primary endpoint was to evaluate the survival landscape of different TRGs after neoadjuvant therapy and the secondary endpoint was to evaluate the associations between pCR and survival. IPD were reconstructed with Kaplan-Meier curves. RESULTS: The 10-year overall survival (OS) and 5-year disease-free survival (DFS) were clearly higher in the pCR group than in the non-pCR (npCR) group (80.5% vs. 48.3, 90.1% vs. 69.8%). Furthermore, the OS and DFS increased with improvement in tumor regression after neoadjuvant therapy. According to the IPD, the pCR group had longer OS (HR = 0.240, 95% CI = 0.177-0.325, p < 0.001) and DFS (HR = 0.274, 95% CI = 0.205-0.367, p < 0.001) than the npCR group. Better tumor regression was associated with better survival outcomes (p < 0.005). Direct calculation of published HR values yielded similar results. CONCLUSIONS: Our results indicate a positive relationship between better tumor regressions and improved survival benefits among the npCR group and patients with rectal cancer achieving pCR had much longer OS and DFS than patients achieving npCR, presenting a survival landscape of different TRGs and pCR in rectal cancer after neoadjuvant therapy.


Subject(s)
Neoadjuvant Therapy/mortality , Rectal Neoplasms/mortality , Disease-Free Survival , Humans , Kaplan-Meier Estimate , Neoplasm Grading , Neoplasm Staging , Rectal Neoplasms/pathology , Rectal Neoplasms/surgery , Rectal Neoplasms/therapy , Time Factors
9.
Biomed Res Int ; 2021: 8852699, 2021.
Article in English | MEDLINE | ID: mdl-34337057

ABSTRACT

BACKGROUND: Neoadjuvant (chemo) radiotherapy is used as a standard treatment for locally advanced rectal cancer (LARC), but there is no general consensus on either the efficacy of postoperative adjuvant chemotherapy in patients with LARC after neoadjuvant treatment and surgery, or whether the addition of oxaliplatin to adjuvant chemotherapy provides survival benefits. METHODS: We performed a meta-analysis of data from the PubMed and Embase databases. We included patients with LARC who received neoadjuvant (chemo) radiotherapy and curative surgery. Overall survival (OS), disease-free survival (DFS), toxicity, and compliance were analyzed in the oxaliplatin/fluorouracil- (OX/FU-) based group compared with the FU-based group, and in the chemotherapy group compared with the observation group. RESULTS: Twenty studies were included in the analysis. Our results indicated that adjuvant chemotherapy prolonged OS (hazard ratio [HR] = 0.78, 95%CI = 0.67-0.91) in patients with LARC treated with neoadjuvant (chemo) radiotherapy and surgery compared with those in the observation group. Subgroup analysis showed the same results in both the ypStage II and ypStage III groups. Compared with those in the observation group, patients in the chemotherapy group also showed an increase in DFS (HR = 0.75, 95%CI = 0.60-0.93). No significant increase was observed in OS (HR = 1.04, 95%CI = 0.87-1.24) or DFS (HR = 0.98, 95%CI = 0.76-1.27) when oxaliplatin was added to FU-based adjuvant chemotherapy, as compared with the FU-based treatment, and subgroup analysis also indicated no survival benefits in the clinical stage II, clinical stage III, ypStage II, and ypStage III groups. CONCLUSIONS: For patients with LARC who have already received neoadjuvant (chemo) radiotherapy and curative surgery, adjuvant chemotherapy improves OS over that in the observation group. Adding oxaliplatin to FU-based adjuvant chemotherapy does not confer survival benefits beyond those from FU-based adjuvant chemotherapy.


Subject(s)
Neoadjuvant Therapy , Postoperative Care , Rectal Neoplasms/pathology , Rectal Neoplasms/therapy , Disease-Free Survival , Humans , Neoadjuvant Therapy/adverse effects , Neoplasm Staging , Patient Compliance , Rectal Neoplasms/surgery
12.
Front Genet ; 12: 633812, 2021.
Article in English | MEDLINE | ID: mdl-33815468

ABSTRACT

Enhancer RNAs, a type of long non-coding RNAs (lncRNAs), play a critical role in the occurrence and development of glioma. RNA-seq data from 161 glioblastoma multiforme (GBM) samples were acquired from The Cancer Genome Atlas database. Then, 70 eRNAs were identified as prognosis-related genes, which had significant relations with overall survival (log-rank test, p < 0.05). AC003092.1 was demonstrated as an immune-related eRNA by functional enrichment analysis. We divided samples into two groups based on AC003092.1 expression: AC003092.1 High (AC003092.1_H) and AC003092.1 Low (AC003092.1_L) and systematically analyzed the influence of AC003092.1 on the immune microenvironment by single-sample gene-set enrichment analysis and CIBERSORTx. We quantified AC003092.1 and TFPI2 levels in 11 high-grade gliomas, 5 low-grade gliomas, and 7 GBM cell lines. Our study indicates that AC003092.1 is related to glioma-immunosuppressive microenvironment, and these results offer innovative sights into GBM immune therapy.

13.
Chin Med J (Engl) ; 134(11): 1345-1355, 2021 Apr 20.
Article in English | MEDLINE | ID: mdl-33883408

ABSTRACT

BACKGROUND: Although increasing abnormal expression of circular RNAs (circRNAs) has been revealed in various cancers, there were a small number of studies about circRNAs in gastric cancer (GC). Here, we explored the expression and function of a novel circRNA, circ_0049447, in GC. METHODS: A total of 80 GC tissues and non-tumorous tissues were collected from the First Affiliated Hospital of China Medical University. And all cells were cultured with 10% fetal bovine serum and incubated at 37°C and 5% CO2. The expression of circ_0049447 was quantified by real-time polymerase chain reaction. The biological function of circ_0049447 on proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) was evaluated by cell counting kit-8 (CCK-8), colony formation assay, transwell migration and invasion assay, and Western blotting. Luciferase report assay was used to verify the direct binding between circ_0049447 and predicted microRNA (miRNA). Furthermore, a xenograft mouse model was used to validate the function of circ_0049447 in vivo. RESULTS: We demonstrated that circ_0049447 was downregulated in GC (P < 0.001). The area under the receiver operating characteristic curve reached 0.838, while sensitivity was 82.3% and specificity was 77.2%. CCK-8 and colony formation assay showed that overexpression of circ_0049447 could inhibit the proliferation (P < 0.05). Transwell migration and invasion assay showed upregulated circ_0049447 could impede migration in GC cells (P < 0.05). In addition, overexpression of circ_0049447 could impede GC cell EMT. Upregulation of miR-324-5p in GC specimens and direct binding between miR-324-5p with circ_0049447 proven by luciferase reporter assay indicated that circ_0049447 may inhibit GC by sponging certain miRNA. CONCLUSION: Circ_0049447 acts as a tumor suppressor in GC through reducing proliferation, migration, invasion, and EMT, and it is a promising biomarker for diagnosis.


Subject(s)
Stomach Neoplasms , Animals , Cell Line, Tumor , Cell Proliferation/genetics , China , Epithelial-Mesenchymal Transition/genetics , Mice , Stomach Neoplasms/genetics
14.
Pain Ther ; 10(1): 525-538, 2021 Jun.
Article in English | MEDLINE | ID: mdl-33616874

ABSTRACT

INTRODUCTION: Postoperative pain management is an essential module for perioperative care, especially for enhanced recovery after surgery programs. Continuous wound infiltration (CWI) with local anesthetic may be a promising postoperative analgesic strategy. However, its analgesic efficacy and safety remain debatable. METHODS: Embase and PubMed databases were systematically searched for relevant randomized controlled trials (RCTs). RCTs assessing the analgesic efficacy and safety of CWI with local anesthetic for postoperative analgesia were selected. The outcomes contained pain scores during rest and mobilization, total opioid consumption, time to the first request of rescue analgesia, length of hospital stay, satisfaction with analgesia, time to return of bowel function, postoperative nausea and vomiting, total complication, wound infection, hypotension, and pruritus. The weighted mean difference and risk ratio were used to pool continuous and dichotomous variables, respectively. RESULTS: A total of 121 RCTs were included. CWI with local anesthetic reduced postoperative pain during rest and mobilization at different time points, increased satisfaction with analgesia, shortened recovery of bowel function, and reduced postoperative nausea and vomiting compared with the placebo group, especially for laparotomy surgery. There were no significant differences in these clinical outcomes compared to epidural and intravenous analgesia. CWI with local anesthetic reduced the total opioid consumption and hypotension risk and did not increase total complications, wound infection, or pruritus. CWI with local anesthetic had a better analgesic efficacy without increased side effects for sternotomy surgery. However, CWI with local anesthetic did not translate into favorable analgesic benefits in laparoscopic surgery. CONCLUSION: CWI with local anesthetic is an effective postoperative analgesic strategy with good safety profiles in laparotomy and sternotomy surgery, and thus CWI with local anesthetic may be a promising analgesic option enhancing recovery after surgery programs for these surgeries.


Continuous wound infiltration (CWI) with local anesthetic may be a promising postoperative analgesic strategy, but its effect remains debatable. We performed this meta-analysis based on 121 high-quality articles (RCTs) to evaluate the analgesic efficacy and safety of CWI with local anesthetic. We found that CWI with local anesthetic could reduce postoperative pain, increase satisfaction with analgesia, shorten recovery of bowel function, and reduce postoperative nausea and vomiting, especially for laparotomy surgery. However, CWI with local anesthetic did not show favorable analgesic benefits in laparoscopic surgery.

15.
Aging (Albany NY) ; 13(3): 3501-3517, 2021 01 10.
Article in English | MEDLINE | ID: mdl-33429364

ABSTRACT

Foxp3+ regulatory T cells (Treg) play an important part in the glioma immunosuppressive microenvironment. This study analyzed the effect of Foxsp3 on the immune microenvironment and constructed a Foxp3-related immune prognostic signature (IPS)for predicting prognosis in glioblastoma multiforme (GBM). Immunohistochemistry (IHC) staining for Foxp3 was performed in 72 high-grade glioma specimens. RNA-seq data from 152 GBM samples were obtained from The Cancer Genome Atlas database (TCGA) and divided into two groups, Foxp3 High (Foxp3_H) and Foxp3 Low (Foxp3_L), based on Foxp3 expression. We systematically analyzed the influence of Foxp3 on the immune microenvironment. Least Absolute Shrinkage and Selection Operator (LASSO) Cox analysis was conducted for immune-related genes that were differentially expressed between Foxp3_H and Foxp3_L GBM patients. We found a differential expression of Foxp3 in high-grade glioma tissues. The presence of Foxp3 was significantly associated with poor OS. From the four-gene IPS developed, GBM patients were stratified into low-risk and high-risk groups in both the training set and validation sets. Furthermore, we developed a novel nomogram to evaluate the overall survival in GBM patients. This study offers innovative insights into the GBM immune microenvironment and these findings contribute to individualized treatment and improvement in the prognosis for GBM patients.


Subject(s)
Brain Neoplasms/genetics , Forkhead Transcription Factors/genetics , Glioblastoma/genetics , Tumor Microenvironment/genetics , Brain Neoplasms/immunology , Female , Forkhead Transcription Factors/immunology , Gene Expression Profiling , Glioblastoma/immunology , Humans , Male , Middle Aged , Prognosis , RNA-Seq , Survival Rate , Transcriptome , Tumor Microenvironment/immunology
16.
Gastroenterology ; 160(1): 260-271.e10, 2021 01.
Article in English | MEDLINE | ID: mdl-32956680

ABSTRACT

BACKGROUND AND AIMS: In stomach, metaplasia can arise from differentiated chief cells that become mitotic via paligenosis, a stepwise program. In paligenosis, mitosis initiation requires reactivation of the cellular energy hub mTORC1 after initial mTORC1 suppression by DNA damage induced transcript 4 (DDIT4 aka REDD1). Here, we use DDIT4-deficient mice and human cells to study how metaplasia increases tumorigenesis risk. METHODS: A tissue microarray of human gastric tissue specimens was analyzed by immunohistochemistry for DDIT4. C57BL/6 mice were administered combinations of intraperitoneal injections of high-dose tamoxifen (TAM) to induce spasmolytic polypeptide-expressing metaplasia (SPEM) and rapamycin to block mTORC1 activity, and N-methyl-N-nitrosourea (MNU) in drinking water to induce spontaneous gastric tumors. Stomachs were analyzed for proliferation, DNA damage, and tumor formation. CRISPR/Cas9-generated DDIT4-/- and control human gastric cells were analyzed for growth in vitro and in xenografts with and without 5-fluorouracil (5-FU) treatment. RESULTS: DDIT4 was expressed in normal gastric chief cells in mice and humans and decreased as chief cells became metaplastic. Paligenotic Ddit4-/- chief cells maintained constitutively high mTORC1, causing increased mitosis of metaplastic cells despite DNA damage. Lower DDIT4 expression correlated with longer survival of patients with gastric cancer. 5-FU-treated DDIT4-/- human gastric epithelial cells had significantly increased cells entering mitosis despite DNA damage and increased proliferation in vitro and in xenografts. MNU-treated Ddit4-/- mice had increased spontaneous tumorigenesis after multiple rounds of paligenosis induced by TAM. CONCLUSIONS: During injury-induced metaplastic proliferation, failure of licensing mTORC1 reactivation correlates with increased proliferation of cells harboring DNA damage, as well as increased tumor formation and growth in mice and humans.


Subject(s)
Chief Cells, Gastric/pathology , Metaplasia/etiology , Metaplasia/pathology , Transcription Factors/physiology , Animals , Carcinogenesis , Cell Culture Techniques , Cell Proliferation , Humans , Mice , Mice, Inbred C57BL
17.
J Gastrointest Surg ; 25(4): 900-910, 2021 04.
Article in English | MEDLINE | ID: mdl-32157605

ABSTRACT

PURPOSE: To investigate lipase C hepatic type (LIPC) expression in Borrmann type 4 gastric cancer and its correlation with clinical outcome. The biological roles of LIPC in Borrmann type 4 gastric cancer progression were also investigated. METHODS: We determined LIPC expression in 324 primary gastric cancer tissues and 178 matched adjacent non-tumor tissues by immunohistochemistry. We explored the role of LIPC in Borrmann type 4 gastric cancer cell (OCUM-1) migration, invasion, proliferation, cell cycle, and expression of epithelial-mesenchymal transition-related genes by knocking down LIPC expression. RESULTS: LIPC expression was upregulated in Borrmann type 4 gastric cancer tissues compared with other types of gastric cancer and adjacent non-tumor tissues. High LIPC expression correlated with lymph node metastasis, advanced TNM stage, and poor overall survival in Borrmann type 4 gastric cancer patients. Multivariate analysis demonstrated that high LIPC expression was an independent prognostic factor in patients with Borrmann type 4 gastric cancer. By reducing LIPC expression, OCUM-1 cell invasion and migration were suppressed and Snail and MMP2 expression was downregulated, while E-cadherin expression was upregulated. CONCLUSIONS: High LIPC expression correlates with poor clinical outcome and plays an important role in regulating cell migration and invasion in Borrmann type 4 gastric cancer.


Subject(s)
Stomach Neoplasms , Humans , Immunohistochemistry , Lymphatic Metastasis , Phenotype , Prognosis , Stomach Neoplasms/genetics
18.
Autophagy ; 17(2): 588-589, 2021 02.
Article in English | MEDLINE | ID: mdl-33280496

ABSTRACT

Differentiated cells have evolved paligenosis, a conserved program to return to a stem or progenitor state and reenter the cell cycle to fuel tissue repair. Paligenosis comprises three sequential stages: 1) quenching of MTORC1 activity with induction of massive macroautophagy/autophagy that remodels differentiated cell architecture; 2) induced expression of progenitor/repair-associated genes; 3) MTORC1 reactivation with cell cycle reentry. Here, we summarize work showing that evolutionarily conserved genes - Ddit4 and Ifrd1 - are critical regulators of paligenosis. DDIT4 suppresses MTORC1 function to induce lysosomes and autophagosomes in paligenosis stage 1. As DDIT4 decreases during paligenosis, TRP53 continues MTORC1 suppression until cells are licensed to reenter the cell cycle by IFRD1 suppression of TRP53. Cells with DNA damage maintain TRP53 until either the damage is repaired, or they undergo apoptosis. The concept of paligenosis and identification of paligenosis-dedicated genes may provide new angles to harness tissue regeneration and specifically target tumor cells.


Subject(s)
Apoptosis/physiology , Autophagosomes/metabolism , Cell Cycle/physiology , Cell Differentiation/physiology , Animals , Cell Division/physiology , Cell Proliferation/physiology , Humans , Mechanistic Target of Rapamycin Complex 1/metabolism
19.
Biosci Rep ; 40(9)2020 09 30.
Article in English | MEDLINE | ID: mdl-32885819

ABSTRACT

Transforming growth factor-ß1 (TGF-ß1) is involved in human cancer development and progression. Nonetheless, the role of TGF-ß1 as regards peritoneal metastasis of gastric cancer has not been completely characterized. In the present study, we investigated the exact role of TGF-ß1 on peritoneal metastasis of gastric cancer. The results indicated that human peritoneal mesothelial cells (HPMCs) exposed to TGF-ß1 or serum-free conditional medium (SF-CM) of SGC7901 that produced a large amount of TGF-ß1 became exfoliated, apoptosis and exhibited signs of injury, and the tumor-mesothelial cell adhesion significantly increased. Connective tissue growth factor (CTGF) expression was also increased when HPMCs were exposed to TGF-ß1 or SF-CM of SGC7901. However, these effects were significantly decreased when HPMCs were exposed to SF-CM of SGC7901-TGFßS, a TGF-ß1 knockdown stable cell line. Animal studies revealed that nude mice injected with SGC7901-TGFßS cells featured a smaller number of peritoneal seeding nodules and lower expression of CTGF in ascites than the control cell lines. These findings suggest that TGF-ß1 promotes peritoneal metastasis of gastric cancer and induces CTGF expression. Therefore, blockage of TGF-ß1 or TGF-ß1 signaling pathway might prevent and treat peritoneal metastasis of gastric cancer.


Subject(s)
Connective Tissue Growth Factor/metabolism , Peritoneal Neoplasms/secondary , Peritoneum/pathology , Stomach Neoplasms/pathology , Transforming Growth Factor beta1/metabolism , Animals , Apoptosis , Cell Adhesion , Cell Line, Tumor , Culture Media, Conditioned/metabolism , Culture Media, Serum-Free/metabolism , Epithelial Cells/pathology , Female , Gene Knockdown Techniques , Humans , Mice , Peritoneum/cytology , Transforming Growth Factor beta1/genetics , Xenograft Model Antitumor Assays
20.
Dev Cell ; 55(2): 178-194.e7, 2020 10 26.
Article in English | MEDLINE | ID: mdl-32768422

ABSTRACT

Differentiated cells can re-enter the cell cycle to repair tissue damage via a series of discrete morphological and molecular stages coordinated by the cellular energetics regulator mTORC1. We previously proposed the term "paligenosis" to describe this conserved cellular regeneration program. Here, we detail a molecular network regulating mTORC1 during paligenosis in both mouse pancreatic acinar and gastric chief cells. DDIT4 initially suppresses mTORC1 to induce autodegradation of differentiated cell components and damaged organelles. Later in paligenosis, IFRD1 suppresses p53 accumulation. Ifrd1-/- cells do not complete paligenosis because persistent p53 prevents mTORC1 reactivation and cell proliferation. Ddit4-/- cells never suppress mTORC1 and bypass the IFRD1 checkpoint on proliferation. Previous reports and our current data implicate DDIT4/IFRD1 in governing paligenosis in multiple organs and species. Thus, we propose that an evolutionarily conserved, dedicated molecular network has evolved to allow differentiated cells to re-enter the cell cycle (i.e., undergo paligenosis) after tissue injury. VIDEO ABSTRACT.


Subject(s)
Cell Cycle/physiology , Cell Differentiation/physiology , Cell Division/physiology , Cell Proliferation/physiology , Animals , Cell Transdifferentiation/physiology , Licensure , Mechanistic Target of Rapamycin Complex 1/metabolism
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