Rab27b, a Regulator of Exosome Secretion, Is Associated With Peritoneal Metastases in Gastric Cancer.

BACKGROUND/AIM: Peritoneal metastasis (PM) of gastric cancer (GC) leads to poor clinical outcomes. Tumor-derived exosomes promote metastasis via communication between tumor cells and host cells. In this study, we investigated the effect of Rab27, which is required for exosome secretion, on the PM of GC. MATERIALS AND METHODS: We established a stable knockdown of two Rab27 homologs, Rab27a and Rab27b, in human GC cells (58As9) with a high potential of PM. We examined the level of exosome secretion from Rab27-knockdown 58As9 cells by Western blotting and the ability of Rab27b knockdown to suppress PM in 58As9 cells using a mouse xenograft model. In vitro proliferation and invasion assays were performed in the Rab27b-knockdown cells. Next, Rab27b expression was evaluated in human GC tissues by immunohistochemistry. Finally, we assessed the clinicopathological and prognostic significance of Rab27b expression by RT-qPCR in both our and other TCGA datasets of GC. RESULTS: Rab27a and Rab27b knockdown in 58As9 cells decreased the secretion of exosomes, characterized by the endocytic marker CD63. Rab27b knockdown decreased PM in vivo without affecting the in vitro proliferation or invasion ability of 58As9 cells. In human GC tissues, Rab27b was overexpressed in tumor cells. The overall and recurrence-free survival rates were significantly lower in GC patients with high compared to low Rab27b mRNA expression in our and other TCGA datasets. CONCLUSION: Rab27b expression potentially serves as a poor prognostic biomarker, possibly affecting PM via exosome secretion from GC cells.

Dynamic Alteration in HLA-E Expression and Soluble HLA-E via Interaction with Natural Killer Cells in Gastric Cancer.

BACKGROUND: Some reports showed the immune tolerance of soluble human leukocyte antigen E (HLA-E), but the role that soluble HLA-E plays in gastric cancer (GC) is unknown. We aimed to clarify the molecular mechanism and clinical significance of soluble HLA-E in GC. METHODS: We examined the expression of HLA-E on GC cells and soluble HLA-E under co-culture with natural killer (NK) cells in a time-dependent manner. Changes in NK cell activity were investigated using anti-NK group 2 member A (NKG2A) antibodies in the presence of soluble HLA-E. Expression of soluble HLA-E in the serum of GC patients was determined. RESULTS: Whereas HLA-E expression on GC cells peaked with interferon (IFN)-γ secretion by NK cells in a time-dependent manner, soluble HLA-E was upregulated in conditioned medium. Pre-incubation with anti-NKG2A antibodies increased the activation of NKG2A+ NK cells in the presence of soluble HLA-E. Expression of soluble HLA-E in the serum of GC patients correlated with disease progression. CONCLUSIONS: HLA-E expression dynamically changes on GC cells and in conditioned medium. Furthermore, soluble HLA-E can contribute to immune escape in GC cell lines, which may have significance in clinical practice. Moreover, soluble HLA-E may be a potential prognostic biomarker.

Evaluation of HLA-E Expression Combined with Natural Killer Cell Status as a Prognostic Factor for Advanced Gastric Cancer.

BACKGROUND: The NKG2A/HLA-E pathway functions as an immune checkpoint with potential for inhibition using therapeutic antibodies. Through this pathway, immune cells lose activity, which allows cancers to progress. We aimed to determine whether HLA-E expression combined with NK cell status serves as a prognostic biomarker for gastric cancer (GC). METHODS: We enrolled patients (n = 232) with advanced GC who underwent curative gastrectomy. Immunohistochemical analyses of global HLA-E expression, and the expression of CD56 and CD3 to identify NK cells were performed. Survival analysis was performed to evaluate the significance of HLA-E expression and NK status. RESULTS: Patients with HLA-E-positive was 104 (41.3%) and had significantly worse prognosis of relapse-free survival (RFS) compared with those with HLA-E-negative. Moreover, patients with NK Low status had worse prognoses for RFS compared with those with NK High status. Statistical analysis of RFS demonstrated that HLA-E expression was a significant independent factor for poor prognosis (HR 1.57, 95% CI 1.04-2.36, P = 0.031). Furthermore, HLA-E-positive patients with low NK low status experienced the shortest RFS, particularly those in the upper GC group. CONCLUSIONS: HLA-E served as a prognostic factor after curative resection of GC, and HLA-E expression combined with NK status served as a sensitive prognostic biomarker for advanced GC.

Comprehensive Analysis of Multiple Primary Cancers in Patients With Esophageal Squamous Cell Carcinoma Undergoing Esophagectomy.

OBJECTIVE: The aim of this study was to elucidate the latest epidemiology and risk factors for multiple primary cancers (MPCs), and the association between neoadjuvant chemotherapy (NAC) and postoperative metachronous cancer (PMC) in patients with esophageal squamous cell carcinoma (ESCC) who underwent esophagectomy. SUMMARY OF BACKGROUND DATA: Background data to derive appropriate screening strategies are insufficient. METHODS: This study consisted of 3 retrospective investigations. A total of 766 consecutive patients with ESCC who underwent esophagectomy between April 2005 and December 2019 were eligible for epidemiological analysis. Of these, 688 patients without missing data were analyzed for the risk of MPCs. In total, 364 patients who underwent NAC (115) and no preoperative treatments (249) were investigated for the association between NAC and PMC. RESULTS: Of 766 patients, 288 (38%) patients experienced 357 MPCs in their life. PMCs identified after the completion of 5-year postoperative follow-up were significantly more advanced (P = 0.019). Male sex [hazard ratio (HR) = 3.04, P = 0.038], older age (HR = 2.39, P < 0.001), and diabetes mellitus (HR = 1.76, P = 0.034) were risk factors for preoperative metachronous cancers. Heavy smoking (HR = 1.70, P = 0.014) and drinking (HR = 1.61, P = 0.029) were risk factors for synchronous cancers. NAC significantly reduced PMC incidence ( P = 0.043). NAC showed a trend to contribute to improved survival via reduced deaths from PMCs, although this did not reach significance ( P = 0.082). CONCLUSIONS: ESCC is associated with a high risk of MPCs. Continuing follow-up for PMCs after the completion of 5-year postoperative follow-up is important. NAC may reduce PMCs, representing a novel mechanism for improving survival in patients with locally advanced ESCC.

Prophylactic laparoscopic total gastrectomy for gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): the first report in Asia.

A 41-year-old woman was admitted to our hospital for epigastralgia. She had been admitted to another hospital for fundic gland polyposis (FGP) without any symptoms, and no malignancy had been noted in her previous endoscopy. However, a biopsy performed at our hospital revealed adenocarcinoma, and computed tomography (CT) revealed multiple liver and peritoneal metastases. We clinically suspected gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) and indicated genetic testing. The point mutation in exon 1B of APC was revealed. She was diagnosed with GAPPS with multiple liver metastases and underwent systemic chemotherapy. She has two older brothers who also have FGP. The same genomic mutation was observed in both brothers and their mother, and they were also diagnosed with GAPPS. The brothers underwent prophylactic laparoscopic total gastrectomy with D1 lymph-node dissection.

Long-term survival after multidisciplinary treatments for advanced esophagogastric junction cancer.

Stage IV Gastric/Esophagogastric junction cancer (G/EGJ) has an unfavorable prognosis and poor curability. In this study, we report the case of long-term survival after multidisciplinary treatments for advanced esophagogastric junction cancer. A 53-year-old male patient was diagnosed with HER2 positive advanced esophagogastric junction cancer and mediastinal and paraaortic lymph node metastasis. After systemic chemotherapy for 1 year, minimally invasive esophagectomy was conducted as conversion surgery. However, peritoneal and liver metastasis was observed on 3 months after curative surgery. 2 years after operation, solitary brain metastasis was detected and stereotactic radiosurgery (SRS) using a gamma knife was underwent. After 1 year, despite the continuous administration of Nivolumab, the paraaortic lymph node increased in size again and radiation therapy was conducted. Currently, he is alive and undergoing chemotherapy.

Analysis of the survival and clinical characteristics of colorectal cancer patients with mental disorders.

AIM: Many studies have shown that patients with mental disorders are less likely than non-psychiatric patients to be diagnosed with or treated for various types of cancers because of their low awareness and understanding of the disease as well as reduced ability to cooperate with medical staff. We analyzed the clinical features of patients with colorectal cancer (CRC) and preexisting mental illness. METHODS: All patients underwent primary tumor resection for CRC. We reviewed the records of 68 patients who were diagnosed with mental disorders. The patients' clinicopathological information was compared with that of a control group of 893 CRC patients. RESULTS: There was no significant difference in the overall disease stage at the time of surgery between the groups. However, disease-free survival, cancer-specific survival, and overall survival were significantly worse in the mental disorder group than in the control group (P < .01). In particular, among those with stage III CRC, overall survival was significantly worse in the patients with mental disorders than in the non-psychiatric patients (P < .001). The frequency of complications of ≥grade 2 according to the Clavien-Dindo classification was higher in the SMI group because of postoperative paralytic ileus. CONCLUSIONS: Advanced CRC patients with mental disorders are less likely to receive postoperative adjuvant chemotherapy or treatment for recurrent cancer than CRC patients without mental disorders; therefore, they experience worse outcomes. Collaboration across multiple departments is necessary for managing CRC patients with mental disorders.

Trastuzumab upregulates programmed death ligand-1 expression through interaction with NK cells in gastric cancer.

BACKGROUND: The predictive significance of programmed death ligand 1 (PD-L1) for programmed death 1 (PD-1) inhibitors remains unclear in gastric cancer (GC) due to the dynamic alteration by treatments. We aimed to elucidate the effects of trastuzumab (Tmab) on PD-L1 expression in GC. METHODS: PD-L1 expression was evaluated by multicolour flow cytometry analysis after co-culturing GG cell lines and immune cells with Tmab. IFN-γ in the co-culture experiments was quantified. Immunohistochemistry (IHC) for PD-L1 expression using clinical samples was also performed to confirm PD-L1 alteration by Tmab. RESULTS: PD-L1 expression was significantly upregulated by Tmab in HER2-amplified GC cell lines co-cultured with peripheral blood mononuclear cells (PBMCs). PD-L1 upregulation by Tmab was also observed in the GC cells co-cultured with NK cells in time-dependent manner, but not with monocytes. IFN-γ concentration in conditioned media from co-cultured PBMCs and NK cells with Tmab was significantly higher and anti-IFN-γ significantly suppress the Tmab-induced PD-L1 upregulation. IHC also suggested PD-L1 upregulation after Tmab treatment. CONCLUSIONS: Tmab can upregulate PD-L1 expression on GC cells through interaction with NK cells. These results suggest clinical implications in the assessment of the predictive significance of PD-L1 expression for PD-1 inhibitors.

Two Asian families with gastric adenocarcinoma and proximal polyposis of the stomach successfully treated via laparoscopic total gastrectomy.

Family 1: a 39-year-old woman and her sister were admitted to our hospital for fundic gland polyps (FGPs). Their mother died of gastric cancer with FGPs. We performed repeated biopsies at close intervals, suspecting gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). After a 1-year follow-up, the sisters were diagnosed with gastric cancer with FGP. We performed laparoscopic total gastrectomies with D1+lymph node dissection. Promoter 1B (exon 1B) of the APC gene (chr5: 112,043,224 T>C) contained a point mutation. The sisters were subsequently diagnosed with GAPPS as per the mutational analysis. Family 2 (unrelated to Family 1): a-24-year-old woman was referred for epigastralgia. EGD revealed FGPs localized in the proximal stomach. Pathological biopsy results showed severe dysplasia and adenocarcinoma in situ. Her father was simultaneously diagnosed with FGPs with GC localized in the proximal stomach. We performed laparoscopic total gastrectomies with D1+lymph node dissection. They had the same gene mutation as the family 1. Here, we report two Asian families with GAPPS successfully treated via laparoscopic total gastrectomy.

Oligometastatic recurrence as a prognostic factor after curative resection of esophageal squamous cell carcinoma.

PURPOSE: In recent years, the concept of oligometastasis, which represents limited metastatic disease, has gained much interest. This study focuses on the oligometastatic recurrence (OLR) of esophageal squamous cell carcinoma (ESCC) after esophagectomy. METHODS: From among 514 patients who underwent curative resection for ESCC at our hospital between April 2005 and December 2019, 97 patients with recurrence were enrolled in this study. OLR was defined as fewer than five recurrences in a single organ. We analyzed the prognostic factors for patients with OLR after curative resection of ESCC, especially the relationship between the recurrence pattern and prognosis according to treatment, defined as metastasis-directed therapy (MDT) and chemotherapy with local therapy as combined local therapy (CLT). RESULTS: OLR was identified in 43 (44%) of the 97 patients with recurrence. The OLR group had a significantly better prognosis than the non-OLR group (P = 0.003). Multivariate analysis revealed that OLR was a prognostic factor after recurrence (P = 0.007) and that CLT after recurrence was the only prognostic factor in the OLR group (P = 0.024). CONCLUSIONS: The findings of this study suggest that OLR is a prognostic factor after resection of ESCC and that CLT is a promising treatment modality for patients with OLR after curative resection of ESCC.

Interval laparoscopic appendectomy after antibiotic therapy for appendiceal abscess in elderly patients.

INTRODUCTION: The aim of this study was to evaluate the safety and efficacy of interval laparoscopic appendectomy after antibiotic therapy in elderly patients with appendiceal abscess. METHODS: We retrospectively analyzed data for 50 patients with appendiceal abscess aged ≥18 years who had initially planned to undergo interval laparoscopic appendectomy after antibiotic therapy and 50 patients with appendicitis aged ≥70 years who had undergone early laparoscopic appendectomy. All patients were treated at the National Hospital Organization Kumamoto Medical Center between 2012 and 2018. We compared perioperative outcomes after interval appendectomy between patients aged <70 years and ≥70 years. RESULTS: Clinical progression of appendicitis during antibiotic therapy developed in one patient (2.0%), and recurrent appendicitis after antibiotic therapy for appendiceal abscess occurred in two patients (4.0%). Pathological findings confirmed appendiceal neoplasms in four patients (8.0%). Postoperative infectious complications occurred in 1 of 47 patients (2.1%) who had undergone successful interval laparoscopic appendectomy, and the median length of postoperative hospital stay was 4 days (interquartile range, 3-5 days). There were no significant differences in outcomes after interval appendectomy between patients aged <70 years and ≥70 years. In the secondary analysis, the median length of postoperative hospital stay after interval laparoscopic appendectomy for appendiceal abscess (4 days) was significantly shorter than that after early laparoscopic appendectomy for uncomplicated appendicitis (7 days; P < .001). CONCLUSIONS: Interval laparoscopic appendectomy for appendiceal abscess may be safe and effective in elderly patients without severe comorbidities. Interval appendectomy may be necessary for determining the underlying cause of appendiceal abscess in adults.

Advanced Age Is a Risk Factor for Recurrence After Resection in Stage II Colorectal Cancer.

BACKGROUND/AIM: The number of older patients with colorectal cancer (CRC) is increasing. Stage II CRC is a heterogeneous group of cancers with different prognoses. We aimed to examine older patients in relation to clinical outcome following curative resection in stage II CRC. PATIENTS AND METHODS: We analyzed data for 329 consecutive patients with stage II CRC following curative resection. Recurrence-free survival (RFS) and overall survival (OS) were compared between older patients ≥75 years of age and those <75 years. Cox proportional hazards model was used to compute hazard ratios (HRs) controlling for potential confounders. RESULTS: In the multivariable analyses, patients ≥75 years were independently associated with shorter RFS (multivariable HR=2.56, 95% confidence interval (CI)=1.55-4.31, p<0.001) and OS (multivariable HR=4.36, 95%CI=2.08-9.97, p<0.001) in stage II CRC. CONCLUSION: Older patients were independently associated with shorter RFS and OS following curative resection in stage II CRC.

The role of FBXW7, a cell-cycle regulator, as a predictive marker of recurrence of gastrointestinal stromal tumors.

BACKGROUND: Few reliable prognostic markers have been established despite elucidation of the molecular mechanisms of gastrointestinal stromal tumor (GIST) development. We evaluated F-box and WD repeat domain-containing 7 (FBXW7), a cell-cycle-regulating and tumor suppressor, in GISTs. We aimed to determine the clinical relevance of FBXW7 in GISTs and characterize the molecular mechanism of FBXW7 in a GIST cell line. METHODS: We measured FBXW7 expression in 182 GIST cases, correlated the expression levels with clinicopathological features, and characterized the molecular mechanism underlying suppressed FBXW7 expression in GIST cells in vitro. RESULTS: Of the 182 GISTs, 98 (53.8%) and 84 (46.2%) were categorized in the high and low FBXW7 expression groups, respectively. Compared with the high FBXW7 expression group, the low expression group showed a significantly poorer prognosis in terms of recurrence-free (P = 0.01) and overall (P = 0.03) survival. FBXW7 expression was a significant independent factor affecting the 10-year recurrence-free survival rate (P = 0.04). In vitro, FBXW7-specific siRNAs enhanced c-myc and Notch 1 protein expression and upregulated cell proliferation, invasion, and migration. CONCLUSION: FBXW7 is a potential predictive marker of recurrence after curative resection of GISTs. FBXW7 expression may help identify patients benefitting from adjuvant therapy more precisely compared with a conventional risk stratification model.

Plastin3 is associated with epithelial-mesenchymal transition and poor prognosis in gastric cancer.

The plastin3 (PLS3) gene, which encodes an actin bundling protein known to inhibit cofilin-mediated depolymerization of actin fiber, has been previously reported to serve an important role in the epithelial-mesenchymal transition (EMT) in cancer. The aim of the present study was to determine the clinical significance of PLS3 and its role in regulating EMT, as well as in promoting cell invasion and migration in gastric cancer. The expression of plastin3 mRNA was measured in 163 resected gastric cancer specimens, in order to determine the clinicopathological significance. Furthermore, in vitro invasion and migration assays were performed on gastric cancer cells, which revealed that PLS3 expression was suppressed. The high PLS3 expression group had a higher incidence of advanced tumour stage, cancer differentiation, tumour invasion depth and distant metastases compared with the low PLS3 expression group (P<0.05). In addition, the high PLS3 expression group had a significantly poorer prognosis than the low expression group (P=0.012). Multivariate analysis indicated that high PLS3 expression was an independent prognostic factor for survival. The present study also identified that suppression of PLS3 in gastric cancer cells was associated with decreased cell invasion and migration. The findings from the present study indicate that high expression of PLS3 in gastric cancer is independently associated with a poor prognosis, and that PL3 serves an important role in EMT.

Laparoscopic removal of an ingested fish bone that penetrated the stomach and was embedded in the pancreas: a case report.

BACKGROUND: The gastrointestinal tract can occasionally be perforated or penetrated by an ingested foreign body, such as a fish bone. However, there are very few reported cases in which an ingested fish bone penetrated the gastrointestinal tract and was embedded in the pancreas. CASE PRESENTATION: An 80-year-old male presented with epigastric pain. Computed tomography of the abdomen showed a linear, hyperdense, foreign body that penetrated through the posterior wall of the gastric antrum. There was no evidence of free air, abscess formation, migration of the foreign body into the pancreas, or pancreatitis. As the patient had a history of fish bone ingestion, we made a diagnosis of localized peritonitis caused by fish bone penetration of the posterior wall of the gastric antrum. We first attempted to remove the foreign body endoscopically, but failed because it was not detected. Hence, an emergency laparoscopic surgery was performed. A linear, hard, foreign body penetrated through the posterior wall of the gastric antrum and was embedded in the pancreas. The foreign body was safely removed laparoscopically and was identified as a 2.5-cm-long fish bone. Intraperitoneal lavage was performed, and a drain was placed in the lesser sac. The patient recovered without complications and was discharged on the 7th postoperative day. CONCLUSION: Laparoscopic surgery could be performed safely for the removal of an ingested fish bone embedded in the pancreas.

Increased EZH2 expression during the adenoma-carcinoma sequence in colorectal cancer.

The adenoma-carcinoma sequence, the sequential mutation and deletion of various genes by which colorectal cancer progresses, is a well-established and accepted concept of colorectal cancer carcinogenesis. Proteins of the polycomb repressive complex 2 (PRC2) function as transcriptional repressors by trimethylating histone H3 at lysine 27; the activity of this complex is essential for cell proliferation and differentiation. The histone methyltransferase enhancer of zeste homolog 2 (EZH2), an essential component of PRC2, is associated with the transcriptional repression of tumor suppressor genes. EZH2 expression has previously been reported to increase with the progression of pancreatic intraductal papillary mucinous neoplasm. Thus, we hypothesized that EZH2 expression also increases during the adenoma-carcinoma sequence of colorectal cancer. The present study investigated changes in EZH2 expression during the colorectal adenoma-carcinoma sequence. A total of 47 patients with colorectal adenoma, 20 patients with carcinoma in adenoma and 43 patients with colorectal carcinoma who underwent surgical or endoscopic resection were enrolled in this study. Non-cancerous tissue from the clinical specimens was also examined. The association between EZH2 expression, pathology and expression of tumor suppressor genes during colorectal carcinogenesis were analyzed. Each specimen was immunohistochemically stained for EZH2, proliferation marker protein Ki-67 (Ki-67), cyclin-dependent kinase inhibitor (CDKN) 1A (p21), CDKN1B (p27) and CDKN2A (p16). Total RNA was extracted from formalin-fixed paraffin-embedded blocks and reverse transcription-quantitative polymerase chain reaction analysis of these genes was performed. Ki-67 and EZH2 expression scores increased significantly during the progression of normal mucosa to adenoma and carcinoma (P=0.009), and EZH2 expression score was positively associated with Ki-67 expression score (P=0.02). Conversely, p21 mRNA and protein expression decreased significantly, whereas expression of p27 and p16 did not change significantly. During the carcinogenesis sequence from normal mucosa to adenoma and carcinoma, EZH2 expression increased and p21 expression decreased significantly. EZH2 may therefore contribute to the development of colorectal cancer from adenoma via suppression of p21.

Non-familial juvenile polyposis of the stomach with gastric cancers: a case report.

BACKGROUND: Juvenile polyposis is an autosomal dominant inherited disease characterized by the development of numerous hamartomatous and nonneoplastic polyps of the gastrointestinal tract. Juvenile polyposis has also recently been reported as a predisposition for gastrointestinal cancer. CASE PRESENTATION: A 63-year-old man underwent esophagogastroduodenoscopy because of anemia and hypoalbuminemia during a follow-up for gastric polyposis, which showed multiple reddish polyps and two elevated lesions in the stomach. The elevated lesions were diagnosed as well-differentiated adenocarcinomas by biopsy. He had no specific physical findings or family history. Computed tomography showed gastric wall thickening without lymphadenopathy or distant metastasis. Colonoscopy showed an adenoma in the transverse colon. He underwent laparoscopy-assisted total gastrectomy with Roux-en-Y esophagojejunostomy. The resected specimen revealed numerous variously sized non-pedunculated polyps throughout the stomach, diagnosed histopathologically as hamartomatous polyps. The two elevated lesions were diagnosed as a well-differentiated adenocarcinoma restricted to the mucosa and a well-to-poorly differentiated adenocarcinoma invading the submucosa with prominent lymphatic permeation, respectively. Genetic analysis failed to identify any germline mutations in the genes usually associated with juvenile polyposis, including SMAD4 and BMPR1A. However, based on the few characteristic physical findings and histopathological features, the final diagnosis was juvenile polyposis restricted to the stomach. CONCLUSIONS: This patient represented a rare case of non-familial juvenile polyposis of the stomach with gastric cancers. Juvenile polyposis has malignant potential, and patients should therefore be carefully followed up. Surgical treatment, particularly total gastrectomy, is recommended as a standard treatment in patients with juvenile polyposis of the stomach with gastric cancer.

Overexpression of FGFR1 Promotes Peritoneal Dissemination Via Epithelial-to-Mesenchymal Transition in Gastric Cancer.

BACKGROUND: Peritoneal dissemination (PD) is one of the most common causes of cancer-related mortality in gastric cancer (GC). We aimed to identify PD-associated genes and investigate their role in GC. MATERIALS AND METHODS: We identified FGFR1 as a putative PD-associated gene using a bioinformatics approach. The biological significance of FGFR1 in epithelial-to-mesenchymal transition (EMT) was evaluated according to the correlation with genes that participated in EMT and FGFR1 knockdown experiments. The associations between FGFR1 expression and the clinicopathological features were examined. RESULTS: FGFR1 expression positively correlated with SNAI1, VIM and ZEB1 expression, and negatively correlated with CDH1 expression. Knockdown of FGFR1 suppressed the malignant phenotype of GC cells. High FGFR1 expression significantly correlated with the peritoneal lavage cytology and synchronous PD positivity as well as poor prognosis. CONCLUSION: High FGFR1 expression was associated with PD via promotion of EMT and led to a poor prognosis of GC patients.

PLOD2 as a potential regulator of peritoneal dissemination in gastric cancer.

Peritoneal dissemination is the most common metastatic pattern in advanced gastric cancer (GC) and has a very poor prognosis. However, its molecular mechanism has not been elucidated. Our study investigated genes associated with peritoneal dissemination of GC. We performed combined expression analysis of metastatic GC cell lines and identified Procollagen-lysine, 2-oxoglutarate 5-dioxygenase2 (PLOD2) as a potential regulator of peritoneal dissemination. PLOD2 is regulated by hypoxia-inducible factor-1 (HIF-1) and mediates extracellular matrix remodeling, alignment, and mechanical properties. We analyzed PLOD2 expression immunohistochemically in 179 clinical samples, and found high PLOD2 expression to be significantly associated with peritoneal dissemination, leading to poor prognosis. In an in vivo-collected metastatic cell line, downregulation of PLOD2 by siRNA reduced invasiveness and migration. Hypoxia upregulated PLOD2 mediated by HIF-1, and promoted invasiveness and migration. After exposure to hypoxia, a cell line transfected with siPLOD2 exhibited significantly suppressed invasiveness and migration, despite high HIF-1 expression. These findings indicate that PLOD2 is a regulator of, and candidate therapeutic target for peritoneal dissemination of GC. Although peritoneal dissemination of GC has a very poor prognosis, its molecular mechanism has not been elucidated. We identified PLOD2 regulated by HIF-1 as a potential regulator of peritoneal dissemination of GC. Finally, we showed that PLOD2 promotes cell invasiveness and migration in GC under hypoxia and lead to peritoneal dissemination of GC.