Lymphovascular invasion is associated with poor long-term outcomes in patients with pT1N0-3 or pT2-3N0 remnant gastric cancer: a retrospective cohort study.

BACKGROUND: Lymphovascular invasion (LVI) is a poor prognostic factor in various malignancies. However, its prognostic effect in remnant gastric cancer (RGC) remains unclear. We examined the correlation between LVI and disease prognosis in patients with T1N0-3 or T2-3N0 RGC in whom adjuvant chemotherapy was not indicated and a treatment strategy was not established. METHODS: We retrospectively analyzed patients with T1N0-3 and T2-3N0 RGC who underwent curative surgery at the Kyoto Prefectural University of Medicine between 1997 and 2019 and at the Kyoto Chubu Medical Center between 2009 and 2019. RESULTS: Fifteen of 38 patients (39.5%) with RGC were positive for LVI. Patients with LVI had a significantly poorer prognosis for both overall survival ([OS]: P = 0.006) and recurrence-free survival ([RFS]: P = 0.001) than those without LVI. Multivariate analyses using the Cox proportional hazards model revealed LVI as an independent prognostic factor affecting OS (P = 0.024; hazard ratio 8.27, 95% confidence interval:1.285-161.6) and RFS (P = 0.013; hazard ratio 8.98, 95% confidence interval:1.513-171.2). CONCLUSIONS: LVI is a prognostic factor for patients with T1N0-3 or T2-3N0 RGC. Evaluating LVI may be useful for determining treatment strategies for RGC.

Prognostic impacts of categorized postoperative complications in surgery for gastric cancer.

BACKGROUND: Postoperative complications generally aggravate postoperative prognosis and are correlated with both cancer-specific death and death from other causes. METHODS: Subjects were 197 patients who underwent gastrectomy at Kyoto Chubu Medical Center. Cancer-specific survival (CSS) and non-CSS (NCSS) were compared between cases with and without complications. Major complications were classified into C-com and N-com groups based on their prognostic impact on CSS and NCSS, respectively. Uni- and multivariate analyses were conducted using clinicopathological factors. RESULTS: During the study period, 30 patients (15.2%) died from gastric cancer and 34 (17.3%) died from other causes. The incidence of postoperative complications was 16.8%. Sixteen patients with anastomosis leakage, pancreatic fistula, or organ/space surgical site infection had significantly poorer CSS, whereas 30 patients with pneumonia or passage obstruction had significantly poorer NCSS. These were defined as C-com and N-com cases, respectively. In the uni- and multivariate analyses, C-com was a significant prognostic factor for CSS (p = 0.002, p = 0.039) and N-com was a significant prognostic factor for NCSS (p < 0.0001, p = 0.004). C-reactive protein levels indicated intermediate and severe inflammation in N-com and C-com cases, respectively. CONCLUSION: In N-com cases, surgical stress caused disruption of essential organ function, whereas damage in C-com cases occurred mostly in the abdominal cavity but was a risk for cancer regrowth. Thus, different postoperative complications worsen patient prognosis after gastrectomy in different ways. To optimize surgical outcomes, improved selection of treatment strategies for different complication types may be important.

[Two Cases of Blind Pouch Syndrome after Total Gastrectomy].

Blind loop syndrome(BLS)is one of the complications that can occur after intestinal anastomosis. Patients with the syndrome present with various clinical features, including nutrient malabsorption caused by the blind end as a result of the anastomotic morphology. On the other hand, blind pouch syndrome(BPS)is a subtype of BLS. While it has a similar underlying mechanism, the clinical symptoms of patients with BPS are significantly different from those of patients with BLS; ie, the symptoms develop almost locally without nutrient malabsorption. There have been some reports that dealt with BPS as a disease that was distinct from BLS. Since conservative treatment cannot be expected to produce a curative effect in patients with BPS, it is necessary to administer surgical treatment in many cases. Previous studies have reported that resection of the blind pouch, which caused the local symptoms, was a curative surgical procedure for BPS. In the present study, we report 2 cases of BPS after Roux-en-Y reconstruction during total gastrectomy for gastric cancer patients, that were cured by surgical treatment by creating a bypass to the blind pouch.

Impact of Preoperative Nutritional Indicator on Poor Postoperative Outcomes in Geriatric Patients with Colorectal Cancer.

The present study aimed to analyze the association between preoperative nutritional assessment and poor postoperative outcomes in geriatric patients with colorectal cancer. This retrospective study included 138 patients aged ≥80 years with colorectal cancer who underwent surgery from January 2013 to December 2018. Patients were classified into two groups according to outcomes, poor group and normal group. Clinicopathological factors were compared between the groups, and the relationships of several nutritional indices were examined. There was no significant difference in sex, age, or preoperative comorbidities. There were significant differences in volume of blood loss and proportion of laparoscopic surgery. The group with poor outcomes had significantly higher neutrophil/lymphocyte ratio (NLR) and modified Glasgow prognostic score (mGPS) than the group with normal outcomes. Multivariate analysis revealed that open approach, high NLR, and category D mGPS were independent risk factors of poor postoperative outcomes in elderly patients with colorectal cancer. Our findings indicate that mGPS and NLR could be useful nutritional indicators of short-term outcomes of surgical treatment in geriatric patients with colorectal cancer. They can be evaluated based on albumin and C-reactive protein levels and blood count, which are inexpensive and beneficial to use in routine clinical practice.

[Comparison between Overall Survival and Disease-Specific Survival after Surgery in Gastric Cancer].

BACKGROUND: It has been reported that we should give consideration to death caused by other disease from comparison between overall survival(OS)and disease specific survival(DSS)in several studies. PATIENTS AND METHODS: Relationships between the clinicopathological features of OS and DSS were examined among 197 patients undergoing surgery for gastric cancer. RESULTS: In OS analysis, the Charlson comorbidity index(CCI), pathological T and postoperative complications with Clavien-Dindo Grade≥Ⅲ were associated significantly in multivariate analyses(p=0.009, 0.022, 0.027). On the other hand, in DSS analysis, CCI was not associated, but gender, DG/TG, pathological N and complication were associated significantly( p=0.0002, 0.016, 0.0003, 0.009). CONCLUSION: The complication is a significant prognostic factor of OS and DSS in gastric cancer patients. It is important to pay attention for comorbidities and to prevent the postoperative complications in order to improve the prognosis in gastric cancer surgical therapy.

[Impact of the Age-Adjusted Charlson Comorbidity Index on Postoperative Complications after Gastric Cancer Surgery].

BACKGROUND: The primary objective of this retrospective study was to examine the association between the age-adjusted Charlson comorbidity index(aCCI)score and postoperative complications after gastric cancer surgery. METHOD: A total of 237 patients who underwent distal/total gastrectomy for gastric cancer between 2012 and 2020 were enrolled in this study. The aCCI and CCI were calculated by weighting individual comorbidities. The correlations between the clinicopathologic features, including CCI or aCCI, and postoperative complications were analyzed statistically. RESULTS: Univariate and multivariate analyses demonstrated that both the CCI- and aCCI- high classifications were significant risk factors for postoperative complications. CONCLUSION: The aCCI exhibits a suitable predictive ability for patients undergoing gastric surgery. Although patients with a CCI≤2 showed little risk, patients with an aCCI≥5 were at a high surgical risk and should receive very careful attention for postoperative complication(s).

[A Case of R0 Resection, with Preservation of Bladder Function, of Advanced Rectal Cancer Infiltrating the Bladder with a Single Metastatic Liver Tumor Due to Preoperative Chemotherapy].

A 75-year-old man was diagnosed with advanced rectal cancer infiltrating the bladder and a single metastatic liver tumor. The patient first underwent colostomy followed by 8 cycles of chemotherapy, using a regimen of cetuximab, calcium levofolinate hydrate, fluorouracil and oxaliplatin(Cmab plus mFOLFOX6). This treatment resulted in a partial response(PR). Five months after the first operation, laparoscopic partial hepatectomy(S4), low anterior resection and ileostomy by laparotomy were performed. The pathological findings were T4b, N1b, M1a, H1, ypStage Ⅳa and all surgical margins were negative, so R0 resection was performed for preservation of bladder function. The patient received adjuvant chemotherapy and has survived without recurrence for 10 months after the second operation. The preoperative chemotherapy permitted combined resection of the bladder and urostomy. This is important because a double stoma commonly reduces quality of life. Thus, Cmab plus mFOLFOX6 may be useful as preoperative chemotherapy to preserve bladder function and quality of life.

Functional analysis and clinical significance of sodium iodide symporter expression in gastric cancer.

BACKGROUND: Recent studies have described important roles for the sodium iodide symporter (NIS) in tumor behavior. The objectives of the present study were to investigate the role of NIS in the regulation of genes involved in tumor progression and the clinicopathological significance of its expression in gastric cancer (GC). METHODS: In human GC cell lines, knockdown experiments were conducted using NIS siRNA, and the effects on proliferation, survival, and cellular movement were analyzed. The gene expression profiles of cells were examined using a microarray analysis. An immunohistochemical analysis was performed on 145 primary tumor samples obtained from GC patients. RESULTS: NIS was strongly expressed in MKN45 and MKN74 cells. The depletion of NIS inhibited cell proliferation, migration, and invasion and induced apoptosis. The results of the microarray analysis revealed that various interferon (IFN) signaling-related genes, such as STAT1, STAT2, IRF1, and IFIT1, were up-regulated in NIS-depleted MKN45 cells. Furthermore, the down-regulation of NIS affected the phosphorylation of MAPKs and NF-kB. Immunohistochemical staining showed that NIS was primarily located in the cytoplasm or cell membranes of carcinoma cells, and its expression was related to the histological type or venous invasion. Prognostic analyses revealed that the strong expression of NIS was associated with shorter postoperative survival. CONCLUSIONS: These results suggest that NIS regulates tumor progression by affecting IFN signaling, and that its strong expression is related to a worse prognosis in patients with GC. These results provide an insight into the role of NIS as a mediator and/or a biomarker for GC.

Treatment with antibodies against primary group A streptococcal peritonitis: A case report and a review of the literature.

RATIONALE: Several reports describe severe group A streptococcal (GAS) infections causing septic shock, soft-tissue necrosis, and multiple organ failure known as streptococcal toxic shock syndrome (STSS). However, primary peritonitis with GAS is rare and most of them were undertaken surgical procedure. PATIENT CONCERNS: We herein reported the case of 26-year-old healthy woman with sudden severe abdominal pain and hypotension. Computed tomography (CT) showed that large amount of free fluid in the peritoneal cavity consist with peritonitis, and no free air. DIAGNOSES: Primary peritonitis with GAS. INTERVENTIONS: Proper antibiotic therapy according to blood culture results. OUTCOMES: After antibiotic therapy, the patient recovered well without complications. LESSONS: An appropriate diagnostic approach and prompt antibiotic therapy is essential in GAS primary peritonitis.

[A Case of Giant Liver Metastasis from Gastric Cancer after Surgery for Which Transcatheter Arterial Embolization and Chemotherapy Made Hepatic Resection Possible].

The prognosis of liver metastasis from gastric cancer, which often exhibits incurable factors, is dismal, and no effective therapy exists. We report a case of giant liver metastasis from gastric cancer after surgery, for which transcatheter arterial embolism and chemotherapy(G-SOX)made it possible to perform hepatic resection. The patient was a 78-year-old woman who underwent distal gastrectomy combined with D2 lymphadenectomy at our department in August 2014. She complained of abdominal distension, and a liver metastasis measuring more than 16 cm in diameter was found on computed tomography in April 2015. Transcatheter arterial embolization was performed followed by chemotherapy(9 courses of G-SOX were administered). These therapies were effective, enabling partial hepatic resection to be performed. The patient remains alive and free from recurrence 4 months after surgery. Although no effective therapy exists for liver metastasis from gastric cancer, intensive therapies may enable curative resection.

PKCδ-iPLA2-PGE2-PPARγ signaling cascade mediates TNF-α induced Claudin 1 expression in human lung carcinoma cells.

Claudin 1 (CLDN1) is a critical component of tight junction adhesion complexes that maintains the structural integrity of epithelial cell layers. Dysregulation of CLDN1 is associated with the growth and metastasis of human lung adenocarcinoma. TNF-α treatment was previously shown to increase expression of CLDN1 that mediated lung cancer cell morphology changes and migration. This study aimed to elucidate the molecular mechanisms involved in TNF-α induced CLDN1 expression in human lung carcinoma A549 cells. Chemical inhibition or siRNA downregulation of Src, PI3K, Akt, MAPKs, NFκB, caspase and PKC demonstrated that PKC, specifically PKCδ, is required for TNF-α induced CLDN1 expression. Further investigation of the PKC pathway revealed that CLDN1 expression is enhanced by the downstream molecules iPLA2, PGE2, 15-keto PGE2 and PPARγ. Conversely, inhibition of these molecules decreased CLDN1 expression. Additionally, a wound-healing assay demonstrated that TNF-α stimulation, PKC activation, prostaglandin treatment or PPARγ activation enhanced cell migration. In conclusion, TNF-α induced CLDN1 expression is regulated by the PKCδ-iPLA2-PGE2-PPARγ signaling cascade in human lung carcinoma A549 cells.

Claudin 1 mediates tumor necrosis factor alpha-induced cell migration in human gastric cancer cells.

AIM: To investigate the role of claudin 1 in the regulation of genes involved in cell migration and tumor necrosis factor alpha (TNF-α)-induced gene expression in human gastric adenocarcinoma cells. METHODS: Knockdown experiments were conducted with claudin 1 small interfering RNA (siRNA), and the effects on the cell cycle, apoptosis, migration and invasion were analyzed in human gastric adenocarcinoma MKN28 cells. The gene expression profiles of cells were analyzed by microarray and bioinformatics. RESULTS: The knockdown of claudin 1 significantly inhibited cell proliferation, migration and invasion, and increased apoptosis. Microarray analysis identified 245 genes whose expression levels were altered by the knockdown of claudin 1. Pathway analysis showed that the top-ranked molecular and cellular function was the cellular movement related pathway, which involved MMP7, TNF-SF10, TGFBR1, and CCL2. Furthermore, TNF- and nuclear frctor-κB were the top-ranked upstream regulators related to claudin 1. TNF-α treatment increased claudin 1 expression and cell migration in MKN28 cells. Microarray analysis indicated that the depletion of claudin 1 inhibited 80% of the TNF-α-induced mRNA expression changes. Further, TNF-α did not enhance cell migration in the claudin 1 siRNA transfected cells. CONCLUSION: These results suggest that claudin 1 is an important messenger that regulates TNF-α-induced gene expression and migration in gastric cancer cells. A deeper understanding of these cellular processes may be helpful in establishing new therapeutic strategies for gastric cancer.

xCT, component of cysteine/glutamate transporter, as an independent prognostic factor in human esophageal squamous cell carcinoma.

BACKGROUND: xCT is a component of the cysteine/glutamate transporter, which plays a key role in glutathione synthesis. The objectives of the present study were to investigate the role of xCT in the regulation of genes involved in cell cycle progression and the clinicopathological significance of its expression in esophageal squamous cell carcinoma (ESCC). METHODS: xCT expression in human ESCC cell lines was analyzed by Western blotting and immunofluorescent staining. Knockdown experiments were conducted with xCT siRNA, and the effect on cell cycle was analyzed. The cells' gene expression profiles were analyzed by microarray analysis. An immunohistochemical analysis of 70 primary tumor samples obtained from ESCC patients that had undergone esophagectomy was performed. RESULTS: xCT was highly expressed in TE13 and KYSE170 cells. In these cells, the knockdown of xCT using siRNA inhibited G1-S phase progression. Microarray analysis identified 1652 genes whose expression levels in TE13 cells were altered by the knockdown of xCT. Pathway analysis showed that the top-ranked canonical pathway was the G1/S checkpoint regulation pathway, which involves TP53INP1, CDKN1A, CyclinD1/cdk4, and E2F5. Immunohistochemical staining showed that xCT is mainly found in the nuclei of carcinoma cells, and that its expression is an independent prognostic factor. CONCLUSIONS: These observations suggest that the expression of xCT in ESCC cells might affect the G1/S checkpoint and impact on the prognosis of ESCC patients. As a result, we have a deeper understanding of the role played by xCT as a mediator and/or biomarker in ESCC.

Prognostic significance of p21 expression in patients with esophageal squamous cell carcinoma.

BACKGROUND: Although p21 is an important component that regulates cell-cycle progression, no consensus has been reached about its clinicopathological significance in esophageal squamous cell carcinoma (ESCC). In the present study, we investigated its prognostic significance and correlation with cyclin-D1 (CCND1) expression in ESCC. MATERIALS AND METHODS: The p21 labeling index (LI) was calculated by immunohistochemistry for 69 primary tumor samples obtained from patients with ESCC who had undergone curative esophagectomy, and correlations between p21 LI and various clinicopathological features, prognosis, and CCND1 LI were studied. RESULTS: The p21 LI of these tumors ranged from 2.0% to 57.0% (median=28.4%, mean±SD=27.3% ± 13.0). p21 LI was positively correlated with CCND1 LI. When patients were divided into two groups using a p21 LI cut-off value of 30%, the 5-year survival rate of patients with p21 LI of ≥ 30% was 80.0%, which was significantly higher than that of patients with p21 LI of <30% (55.5%). Furthermore, when patients were divided into four groups according to p21 and CCND1 expression, the 5-year survival rate of patients with p21 LI of <30% and CCND1 LI of ≥ 45% was the lowest (44.4%). Multivariate analysis demonstrated that venous invasion, lymphatic invasion, and p21 LI were independent prognostic factors. CONCLUSION: Our results indicate that p21 LI is correlated with CCND1 LI and can be used as an independent prognostic factor for patients with ESCC following selection of a suitable cut-off value.

XB130, a new adaptor protein, regulates expression of tumor suppressive microRNAs in cancer cells.

XB130, a novel adaptor protein, promotes cell growth by controlling expression of many related genes. MicroRNAs (miRNAs), which are frequently mis-expressed in cancer cells, regulate expression of targeted genes. In this present study, we aimed to explore the oncogenic mechanism of XB130 through miRNAs regulation. We analyzed miRNA expression in XB130 short hairpin RNA (shRNA) stably transfected WRO thyroid cancer cells by a miRNA array assay, and 16 miRNAs were up-regulated and 22 miRNAs were down-regulated significantly in these cells, in comparison with non-transfected or negative control shRNA transfected cells. We chose three of the up-regulated miRNAs (miR-33a, miR-149 and miR-193a-3p) and validated them by real-time qRT-PCR. Ectopic overexpression of XB130 suppressed these 3 miRNAs in MRO cells, a cell line with very low expression of XB130. Furthermore, we transfected miR mimics of these 3 miRNAs into WRO cells. They negatively regulated expression of oncogenes (miR-33a: MYC, miR-149: FOSL1, miR-193a-3p: SLC7A5), by targeting their 3' untranslated region, and reduced cell growth. Our results suggest that XB130 could promote growth of cancer cells by regulating expression of tumor suppressive miRNAs and their targeted genes.

Anti-phosphohistone H3 as an independent prognostic factor in human esophageal squamous cell carcinoma.

BACKGROUND: The immunohistochemical staining of phospho-histone H3 (PHH3) has recently been reported to predict the prognosis of different tumors. However, it has not been evaluated in esophageal squamous cell carcinoma (ESCC). The aim of this study was to evaluate the prognostic impact of PHH3 in ESCC. MATERIALS AND METHODS: The number of anti-phophohistone H3-positive nuclei [i.e. PHH3 mitotic index (MI)] was calculated by immunohistochemistry of 50 primary tumor samples obtained from patients with ESCC who underwent curative esophagectomy. RESULTS: The PHH3 MI per 10 high-power fields ranged from 1 to 72 (median=15.5). When the patients were divided into two groups using a cut-off value of 10, the 5-year survival rate of the patients with PHH3 MI ≤10 was significantly higher than that of patients with PHH3 MI >10. Multivariate analysis indicated PHH3 MI to be an independent prognostic factor. CONCLUSION: The expression of PHH3 impacts the prognosis of patients with ESCC.

XB130 as an independent prognostic factor in human esophageal squamous cell carcinoma.

BACKGROUND: Adaptor proteins, with multimodular structures, can participate in the regulation of various cellular functions. A novel adaptor protein XB130 has been implicated as a substrate and regulator of tyrosine kinase-mediated signaling and in controlling cell proliferation and apoptosis in thyroid and lung cancer cells. However, its expression and role in gastrointestinal cancer have not been investigated. We sought to determine the role of XB130 in cell cycle progression of esophageal squamous cell carcinoma (ESCC) cells and to examine its expression and effects on the prognosis of patients with ESCC. METHODS: Expression of XB130 in human ESCC cell lines was analyzed by Western blot testing and immunofluorescent staining. Knockdown experiments with XB130 small interfering RNA (siRNA) were conducted, and the effect on cell cycle progression was analyzed. Immunohistochemistry of XB130 for 52 primary tumor samples obtained from patients with ESCC undergoing esophagectomy was performed. RESULTS: XB130 was highly expressed in TE2, TE5, and TE9 cells. In these cells, knockdown of XB130 with siRNA inhibited G1-S phase progression and increased the expression of p21, the cyclin-dependent kinase inhibitor. Immunohistochemistry showed that 71.2% of the patients expressed XB130 in the nuclei and/or cytoplasm of the ESCC cells. Further, nuclear expression of XB130 was an independent prognostic factor of postoperative survival. CONCLUSIONS: These observations suggest that the expression of XB130 in ESCC cells may affect cell cycle progression and impact prognosis of patients with ESCC. A deeper understanding of XB130 as a mediator and/or biomarker in ESCC is needed.

Case involving long-term survival after esophageal cancer with liver and lung metastases treated by multidisciplinary therapy: report of a case.

A 57-year-old male with lower esophageal cancer underwent subtotal esophagectomy with lymphadenectomy. The histopathological diagnosis was poorly differentiated squamous cell carcinoma, pT2N1M0 pStageIIB. After one course of postoperative adjuvant chemotherapy involving low-dose CDDP/5FU, a PET-CT scan obtained 12 months after surgery revealed a solitary liver metastasis in the S2 area. The patient then underwent five courses of docetaxel chemotherapy (80 mg/body, tri-weekly), and a partial response was observed. We also performed radiofrequency ablation (RFA), after which a complete response was observed. Twenty months after surgery, we detected local liver recurrence in the same position and performed additional RFA. Twenty-four months after surgery, a solitary lung metastasis was detected in the left S2 area and the patient was administered five additional courses of docetaxel therapy. Subsequently, PET-CT revealed growth of lung and liver tumors without recurrence in other areas. Twenty-nine months after surgery, we partially excised metastatic liver and lung tumors, and no subsequent recurrence has since been detected. The prognoses of patients who suffer from esophageal cancer organ recurrence are known to be extremely poor, and optimal therapeutic strategies for treating these patients have not been established. This long-term survival case suggests that multidisciplinary therapy for the treatment of liver and lung recurrence after esophagectomy is effective.

Enhancement of the cytocidal effects of hypotonic solution using a chloride channel blocker in pancreatic cancer cells.

BACKGROUND: Tumor cells exfoliated during surgery for pancreatic cancer can cause peritoneal recurrence. Peritoneal lavage with distilled water has been performed during surgery, but there have been no systematic studies for its efficacy and no experimental data demonstrating the cytocidal effects of distilled water on pancreatic cancer cells. This study investigated the cytocidal effects of hypotonic shock and enhancement using chloride channel blocker in pancreatic cancer cells. METHODS: Three human pancreatic cancer cell lines, KP4-1, PK-1, and PK45-H, were exposed to distilled water, and the resultant morphological changes were observed under a differential interference contrast microscope connected to a high-speed video camera. Analysis of cell volume changes was performed using a high-resolution flow cytometer. To investigate the cytocidal effects of water, re-incubation of cells was performed after exposure to hypotonic solution. Additionally, the effects of 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), a Cl(-) channel blocker, on cells during exposure to hypotonic solution were analyzed. RESULTS: Video recordings demonstrated that hypotonic shock induced cell swelling followed by cell rupture. Measurement of cell volume changes indicated that severe hypotonicity increased broken fragments of cancer cells within 5 min. Re-incubation experiments demonstrated the cytocidal effects of hypotonic shock. In all cell lines, treatment with NPPB increased cell volume by inhibiting regulatory volume decreases, which are observed during hypotonic shock, and enhanced the cytocidal effects of hypotonic solution. CONCLUSIONS: These findings support the efficacy of peritoneal lavage with distilled water for pancreatic cancer and suggest that regulation of Cl(-) transport enhances the cytocidal effects of hypotonic shock.

XB130 mediates cancer cell proliferation and survival through multiple signaling events downstream of Akt.

XB130, a novel adaptor protein, mediates RET/PTC chromosome rearrangement-related thyroid cancer cell proliferation and survival through phosphatidyl-inositol-3-kinase (PI3K)/Akt pathway. Recently, XB130 was found in different cancer cells in the absence of RET/PTC. To determine whether RET/PTC is required of XB130-related cancer cell proliferation and survival, WRO thyroid cancer cells (with RET/PTC mutation) and A549 lung cancer cells (without RET/PTC) were treated with XB130 siRNA, and multiple Akt down-stream signals were examined. Knocking-down of XB130 inhibited G(1)-S phase progression, and induced spontaneous apoptosis and enhanced intrinsic and extrinsic apoptotic stimulus-induced cell death. Knocking-down of XB130 reduced phosphorylation of p21Cip1/WAF1, p27Kip1, FOXO3a and GSK3ß, increased p21Cip1/WAF1protein levels and cleavages of caspase-8 and-9. However, the phosphorylation of FOXO1 and the protein levels of p53 were not affected by XB130 siRNA. We also found XB130 can be phosphorylated by multiple protein tyrosine kinases. These results indicate that XB130 is a substrate of multiple protein tyrosine kinases, and it can regulate cell proliferation and survival through modulating selected down-stream signals of PI3K/Akt pathway. XB130 could be involved in growth and survival of different cancer cells.