Fuzheng Huayu recipe inhibits bleomycin-induced pulmonary fibrosis in rats by inhibiting M2 polarization of macrophages via the oxidative phosphorylation pathway.

Fuzheng Huayu recipe (FZHYR) is a Chinese patent medicine for the treatment of fibrosis. The effects of FZHYR on pulmonary fibrosis and macrophage polarization were investigated in vitro. FZHYR inhibited pulmonary inflammation and fibrosis and M2 polarization of macrophages in bleomycin-induced pulmonary fibrosis (BPF) of rat model. Differentially expressed genes were screened by high-throughput mRNA sequencing and GSEA showed that oxidative phosphorylation (OXPHOS) was correlated with BPF. FZHYR inhibited expressions of Ndufa2 and Ndufa6 in lung tissues of BPF rats. These findings suggest that OXPHOS pathway serves as a possible target for pulmonary fibrosis therapy by FZHYR.

Gelstriamine A, a Triamino Monoterpene Indole Alkaloid with a Caged 6/5/7/6/6/5 Scaffold and Analgesic Alkaloids from Gelsemium elegans Stems.

A novel triamino monoterpene indole alkaloid with an unprecedented skeleton, gelstriamine A (1), four new monoterpene indole alkaloids (2-5), and 12 known analogues (6-17) were isolated from Gelsemium elegans. The structures of 1-5 were established using extensive spectroscopic techniques, NMR calculations with iJ/dJ-DP4 and 2D C-H COSY ANNs analysis, ECD calculations, chemical methods, and single crystal X-ray diffraction analysis. Gelstriamine A (1) possesses an unprecedented 6/5/7/6/6/5 heterohexacyclic scaffold bearing a unique hexahydrooxazolo[4,5-b]pyridin-2(3H)-one motif, and a plausible biosynthetic pathway was proposed. All the isolated alkaloids 1-17 showed discernible analgesic activities in an acetic acid-induced writhing test in mice, and N-desmethoxyhumantenine N4-oxide (3) exhibited more potent analgesic activities than those of morphine at doses of 0.04 and 0.2 mg/kg.

Structurally diverse diterpenoids with eight carbon skeletons from Rhododendron micranthum and their antinociceptive effects.

Seventeen diterpenoids (1-17), classified into eight diverse carbon skeleton types, grayanane (1, 2, and 12), micranthane (3, 4, and 13), mollane (5-7 and 14), 1,5-seco-grayanane (8), kalmane (9-11), 1,5-seco-kalmane (15), A-homo-B-nor-ent-kaurane (16), and leucothane (17), respectively, were isolated from the leaves extract of Rhododendron micranthum. Among them, diterpenoids 1-9 are new compounds and their structures were elucidated via extensive spectroscopic methods, quantum chemical calculations including the 13C NMR-DP4+ analysis and electronic circular dichroism (ECD) calculations, and the single-crystal X-ray diffraction analysis. Micranthanol A (1) represents the first example of a 5αH,9αH-grayanane diterpenoid and a 6-hydroxy-6,10-epoxygrayanane diterpenoid, and micranthanone B (3) is the first 6,10-epoxymicranthane and the 5α-hydroxy-micranthane diterpenoids. 14-epi-Mollanol A (5) and mollanol B (6) represent the first examples of 14ß-hydroxymollane diterpenoids. It is the first time to report mollane, 1,5-seco-kalmane, and A-homo-B-nor-ent-kaurane type diterpenoids from Rhododendron micranthum. All the seventeen diterpenoids showed significant antinociceptive activities at a dose of 5.0 mg/kg, and it is the first time to evaluate the antinociceptive activity of 1,5-seco-kalmane diterpenoid. Among them, compounds 3, 11, 14, and 15 exhibited significant antinociceptive activities even at a lower dose of 1.0 mg/kg. A preliminary structure-activity relationship for the antinociceptive effects of diterpenoids 1-17 is discussed, which provided a new basis to develop novel potent analgesics.

Vasoactive intestinal peptide stimulates melanogenesis in B16F10 mouse melanoma cells via CREB/MITF/tyrosinase signaling.

Vasoactive intestinal peptide (VIP), one of the major skin neuropeptides, has been suggested to have active roles in the pathogenesis of inflammatory skin disorders such as atopic dermatitis and psoriasis, which can commonly cause post-inflammatory hyperpigmentation. However, the effect of VIP on melanogenesis remains unknown. In this study, we showed that the melanin contents, tyrosinase activity, and gene expression of tyrosinase and microphthalmia-associated transcription factor (MITF) were significantly increased by treatment with VIP in B16F10 mouse melanoma cells and the stimulatory melanogenic effect was further examined in human epidermal melanocytes (HEMns). In addition, phosphorylated levels of CRE-binding protein (CREB) and protein kinase A (PKA) were markedly increased after VIP treatment, but not p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), or Akt, indicating the possible PKA-CREB signaling pathway involved in VIP-induced melanogenesis. This result was further verified by the fact that VIP induced increased melanin synthesis, and protein levels of phosphorylated CREB, MITF, tyrosinase were significantly attenuated by H89 (a specific PKA inhibitor). These data suggest that VIP-induced upregulation of tyrosinase through the CREB-MITF signaling pathway plays an important role in finding new treatment strategy for skin inflammatory diseases related pigmentation disorders.

The de-ubiquitinase UCHL1 promotes gastric cancer metastasis via the Akt and Erk1/2 pathways.

Ubiquitin C-terminal hydrolase-L1 (UCHL1) is a de-ubiquitinating enzyme, which enzymatic activity relies on the C90 site. The function of UCHL1 is controversial in different types of cancer, and its role in gastric cancer progression remains unclear. In this study, immunohistochemistry staining was applied to detect the expression of UCHL1 in primary gastric cancer and liver metastases from gastric cancer. MKN45 and BGC823 cell lines with stable expression of de-ubiquitinase active UCHL1 or inactive UCHL1-variant C90S were established by lentiviral infection. The effect of UCHL1 on cell proliferation was evaluated by MTT and colony formation assays. The abilities of cell migration and invasion were determined by transwell assay. Protein expression levels were determined by Western blot. The results indicated that UCHL1 had a significantly higher positive expression rate in liver metastases from gastric cancer compared with primary gastric cancer. Overexpression of UCHL1 in MKN45 and BGC823 cells promoted cell proliferation, migration, and invasion depending on its de-ubiquitinase activity. UCHL1 activated Akt and Erk1/2, which process also required enzymatic activity and was necessary for mediating cell migration and invasion. These findings demonstrated that UCHL1 promoted cell proliferation, migration, and invasion depending on its de-ubiquitinase activity by activating Akt and Erk1/2, which may account for its higher positive expression rate in liver metastases from gastric cancer. UCHL1 could be a candidate biomarker and a therapeutic target for gastric cancer metastasis.

Comparison study of fractional carbon dioxide laser resurfacing using different fluences and densities for acne scars in Asians: a randomized split-face trial.

BACKGROUND: Ablative 10,600-nm carbon dioxide (CO2 ) fractional laser treatments have shown favorable outcomes for atrophic acne scars. OBJECTIVE: To compare the efficacy and complications of fractional CO2 laser treatments with different fluences and densities for acne scars. METHODS: Twenty patients were treated using a single session of fractional CO2 laser in Deep FX mode. In Group A (n = 10), half of the face was treated with 20 mJ, density 10% and the other half with 20 mJ, density 20%. In Group B (n = 10), half of the face was treated with 10 mJ, density 10% and the other half with 20 mJ, density 10%. Patients were evaluated at baseline and 3 days, 1 week, 1 month, and 3 months after the procedure. RESULTS: There was no significant difference in efficacy between different laser settings within the groups, although adverse effects were more evident in patients treated with higher densities or fluences. CONCLUSION: Factional CO2 laser treatment using the Deep FX mode may provide a significant efficacy with lower fluence and density with fewer complications than with higher energies for acne scars.

CCDC134 is down-regulated in gastric cancer and its silencing promotes cell migration and invasion of GES-1 and AGS cells via the MAPK pathway.

CCDC134 (coiled coil domain containing 134), a novel secretory protein, acts as an inhibitor of Erk1/2 and JNK/SAPK pathways. However, the role of CCDC134 in cancer development is still lacking. In this study, we found that CCDC134 expression significantly reduced in gastric cancer tissues compared with normal tissues (P < 0.001) and lesion tissues (P < 0.001). But no statistically significant difference was observed between normal and lesion tissues (P = 0.842). In vitro transient transfection of CCDC134-specific siRNA significantly promoted the migration and invasion of both the normal gastric epithelial cell line GES-1 and gastric cancer cell line AGS cells. Further analysis revealed that the attenuated expression of CCDC134 promoted the activation of Erk1/2 and JNK/SAPK, but had no effect on p38. The activation of Erk1/2 and JNK/SAPK was required for CCDC134-mediated migration and invasion. Besides, CCDC134-RNAi could induce the expression of MMP-2 and MMP-9, which are key molecules involved in regulating cell migration and invasion. Therefore, CCDC134 may be a candidate biomarker for malignant transformation. It plays a role in regulation of cell migration and invasion, and could be a therapeutic target of gastric cancer.

[Diagnosis and treatment of primary colorectal non-Hodgkin's lymphoma: analysis of 52 cases].

OBJECTIVE: To summarize and analyze the diagnosis, clinical features and therapy of primary colorectal non-Hodgkin's lymphoma (NHL). METHODS: The clinicopathological data of 52 patients with primary colorectal NHL diagnosed and treated in our department from January 2000 to January 2010 were reviewed and analyzed retrospectively in this study. RESULTS: This group of patients was composed of 45 cases of B cell and 7 T cell lymphomas, including 33 males and 19 females, with a male to female ratio of 1.7:1, and the age at diagnosis was 16 - 74 years old, with a median age of 50 years. The ileocecal region was most frequently involved site, acounted for 48.1%. The common symptoms encountered were abdominal pain (66.7%), diarrhea (15.6%), blood stool (24.4%), and body weight loss (8.9%). All patients were eventually diagnosed by histopathology, and the DLBCL subtype took up 64.4%. Among the 45 cases of B cell subtype, 33 cases (73.3%) were of early stage (IE and IIE confirmed), and the 5-year survival rate was 78.1%, while those of stage IIIE and IVE comprised 26.7%, with a 5-year survival rate of 45.5% (P < 0.05). The 5-year survival rate of all patients was 71.1%. Surgery was employed in 36 cases, and 9 patients received chemotherapy alone. Radical surgery could significantly increase the patients' overall survival rate, as compared with the chemotherapy alone group and palliative surgery group (P < 0.05). CONCLUSIONS: Colorectal non-Hodgkin's lymphoma is a rare malignancy of the gastrointestinal tract. B cell type, male predominance and DLBCL subtype are most encountered manifestations in clinics. Multi-modality management with radical surgical resection of the primary lesion followed by standard chemotherapy, affords better local disease control, and a better survival outcome. Early detection and tailored immunotherapy can obviously prolong the long-term survival time.

[Clinical analysis of 17 cases of gastric small cell carcinoma].

OBJECTIVE: To analyze the clinical data and prognosis of gastric small cell carcinoma (GSCC), summarize recent progress in diagnosis and therapy of this disease reported in the literature, and to provide the theoretical basis for its appropriate treatment. METHODS: Clinicopathological data of 17 patients with pathologically confirmed GSCC, treated in our hospital between 1999 to 2012, were retrospectively reviewed. RESULTS: There were 16 males and 1 female, ranged from 46 to 75 years (mean 64.6 years). The tumor was located in the gastric cardia in 13 cases, three in the gastric fundus, and one in the gastric body. All the 17 patients received surgery and 10 of them received postoperative adjuvant chemotherapy, one received preoperative adjuvant chemotherapy. Thirteen patients were followed up. Among them, two 1ived for 40 months all along, the other 3 cases died of recurrence and extensive metastasis in 6 month after operation. The median survival was 13.0 months. The median survival of the patients with and without lymph node metastasis were 42 months and 13 months, respectively. The median survival time of stage II and III patients were 24 months and 14 months, respectively. CONCLUSIONS: It is difficult to make a definite diagnosis before or during the operation for GSCC. Radical operation could be done according to other gastric cancers and lymph node dissection could be simplified. Postoperative chemotherapy with the same scheme as lung small cell carcinoma may help to improve the outcome and prolong the survival of the patients.

[The diagnosis, treatment and prognosis evaluation of gastric small cell carcinoma: analysis of 41 cases].

OBJECTIVE: To summarize and analyze the clinical feature, therapeutic methods and prognosis of gastric small cell carcinoma (SCC). METHODS: The clinical and pathological data of 41 patients diagnosed of gastric SCC were analyzed in this research. Also, the factors which may potentially affect the patients' survival outcome were evaluated. There were 35 male and 6 female patients. The age at diagnosis was 39-84 years, median age was 62 years. The 31 cases (75.6%) of gastric SCC patients were involved in the upper third of the stomach, 3 cases (7.3%) in the middle, 7 cases (17.1%) in the lower third. RESULTS: The time from the event of symptoms to final confirmation was 1 to 13 months, the median time was 3 months. The longest diameter of tumors was from 2.5 to 15.0 cm, the average was 6.5 cm. The 38 cases (92.7%) chosed surgery as the first treatment, among which 25 cases (61.0%) were performed radical tumor resection, 13 cases (31.7%) went through palliative resection, and 3 cases (7.3%) just employed chemotherapy. The initial II, III, IV stage were 2, 31 and 8 cases, respectively. The overall median survival time was 19 months, median disease free survival time was 11 months, 1-, 2-, 5-years survival rates were 70.7%, 46.3% and 36.6%, respectively. In univariate survival analysis, the tumor size (χ² = 5.565), change of the body weight (χ² = 3.688), type of operation (χ² = 11.747) and relapse or not (χ² = 17.966) were obviously correlaed with the prognosis (P < 0.05). CONCLUSIONS: Gastric SCC is a rare disease of the gastrointestinal tract, the misdiagnosis rate is high, and the prognosis is dismal. Muti-modality management, with radical surgical resection of the primary lesion followed by standard adjuvant-chemotherapy, affords better local disease control and a better survival outcome.

Oleanolic acid regulates the proliferation and extracellular matrix of keloid fibroblasts by mediating the TGF-ß1/SMAD signaling pathway.

BACKGROUND: Keloid (KD) is a unique pathological fibroproliferative disease that seriously affects the appearance of patients. This study investigated the effect of oleanolic acid (OA) on the proliferation of keloid fibroblasts (KFs) and the expression of extracellular matrix (ECM)-related proteins. METHODS: The proliferation of KFs was evaluated using an MTT assay. The effects of OA on intra- and extracellular levels of fibronectin (FN), procollagen I, matrix metalloproteinase-1 (MMP-1), and α-smooth muscle actin (α-SMA) were evaluated using Western blotting. To simulate the KD microenvironment, TGF-ß1 was added to the serum-free culture medium, and KFs were incubated with TGF-ß1 and OA for 24 h. The intra- and extracellular levels of the ECM-related proteins and the effect of OA on TGF-ß1-induced phosphorylation of the SMAD2 and SMAD3 proteins were evaluated using Western blotting. RESULTS: OA inhibited the proliferation of KFs in a concentration- and time-dependent manner. Furthermore, OA treatment of KFs reduced the intra- and extracellular levels of FN, procollagen I, and α-SMA and increased those of MMP-1. OA also reduced TGF-ß1-induced increases in the intra- and extracellular levels of FN, procollagen I, and α-SMA and increased the levels of the MMP-1 protein. Additionally, OA significantly reduced TGF-ß1-induced phosphorylation of SMAD2 and SMAD3 in KFs. CONCLUSIONS: OA inhibited KF proliferation and reduced ECM deposition through the TGF-ß1/SMAD pathway, which suggests that OA may be an effective drug for the prevention and treatment of KD.

Primary small cell carcinoma of the stomach: an experience of two decades (1990-2011) in a Chinese cancer institute.

BACKGROUND: Primary gastric small cell carcinoma (GSCC) is a rare and aggressive disease for which the standard treatment has not been established. The objective of this study is to investigate the clinical characteristics and survival. METHODS: All cases of GSCC treated at our institute from January 1990 to December 2011 were reviewed and analyzed retrospectively. Statistical analyses were performed using Fisher's exact test. RESULTS: A total of 19 patients from 11,603 cases (0.16%) of all gastric cancers treated during this period were identified. The median age was 61 years and the patients were predominantly men. Using the latest AJCC Staging Criteria, the majority of the patients (68.4%) were Stage III. All patients underwent surgery. The median overall survival time (MST) was 19.5 months (95% CI 17.5-21.6 months). The 1-, 3-, and 5-year overall survival rates were 77.3%, 44.2%, and 22.1%, respectively. The MST of 48.5 months for cases who received postoperative adjuvant chemotherapy was superior to that of 19.0 months for cases who did not (P = 0.026). CONCLUSIONS: Our data indicate that GSCC patients can be treated effectively with combined modality of treatment, despite the aggressive nature of GSCC. Systemic therapy, based on chemotherapy with surgery, is recommended.

[Phase II clinical trial of docetaxel, platinum and S-1 for advanced gastric cancer].

OBJECTIVE: To evaluate the efficacy and safety profile and to explore the role of docetaxel, S-1 plus cisplatin (DCS) or oxaliplatin (DOS) in the treatment of advanced gastric cancer. METHODS: A total of 45 patients with advanced gastric cancer were recruited. They received DCS or DOS at the discretion of investigators. Docetaxel was given intravenously at the dose of 60 mg/m² at d1, S-1 60 mg×m⁻²×d⁻¹ or 80 - 120 mg/d according to individual patient's area of body surface orally from d1 to d14 and cisplatin 30 mg/m² at d1, d2 or oxaliplatin 111 - 127 (median: 117) mg/m ²at d2. Each cycle was for 21 days. RESULTS: Forty-three patients received ≥ 1 complete cycle of DCS/DOS with a median cycle number of 5(range: 1 - 8). Among 42 patients evaluated for efficacy, the outcomes were partial response (n = 28), stable disease (n = 9) and progression (n = 5). The response rate was 66.7%. Progression-free survival (PFS) of 32 patients on chemotherapy alone was 7.1 months and the median overall survival (OS) was not reached. The most common grade 3/4 adverse effects included neutropenia (46.5%), thrombocytopenia (9.3%), vomiting (9.3%), nausea (7.0%) and diarrhea (4.7%). Ten of fourteen patients with advanced unresectable gastric cancer without clinically detectable distant metastases underwent surgical resection after a median of 4 (2-6) cycles of DCS or DOS and 9 (64.3%) had R0 resection. CONCLUSIONS: DCS/DOS is effective for advanced gastric cancer and in the setting of neoadjuvant chemotherapy. And the toxicities of DCS/DOS are manageable.

Proteomic profiling of proteins associated with lymph node metastasis in colorectal cancer.

Lymph node metastasis (LNM) is associated with poor prognosis in colorectal cancer (CRC). The presence or absence of lymph node metastases is a strong independent prognostic factor for CRC survival. Investigation of proteins associated with the process of lymph node metastasis (LNM) is crucial for understanding of the molecular mechanisms underlying the LNM process and for predicting the CRC prognosis. In the present study, proteins from CRC tissues and adjacent normal mucosa (NMC) were examined using two-dimensional gel electrophoresis coupled with MALDI-TOF-MS. The expression levels of Ferritin Heavy Chain (FHC) were decreased in LNM CRC as compared to those in non-LNM CRC, while the expression of Cathepsin D and Ubiquitin C-terminal hydrolase-L1 (UCH-L1) were increased in LNM CRC. The results were confirmed by Western blotting and immunohistochemical staining. Furthermore, in vitro cell invasion assay showed that the overexpression of UCH-L1 through gene transfection increased the invasive ability of HCT8 cells, suggesting that UCH-L1 is not only a biomarker for LNM in CRC, but also a functional protein that may play a significant role in cell migration. The proteins identified in the present study should further our understanding of the LNM process of CRC and may become useful markers for diagnosis and targets for therapeutic interventions.

Overexpression of PIP5KL1 suppresses the growth of human cervical cancer cells in vitro and in vivo.

PIP5KL1 (phosphatidylinositol-4-phosphate 5-kinase-like 1), the fourth member of PIP5Ks (phosphatidylinositol-4-phosphate 5-kinases) type I, acts as a scaffold for localization and activation of PIP5Ks, which in turn regulate numerous cellular processes. However, the role of PIP5KL1 in the development of human cancer is poorly studied. In this study, we established a stable clone of PIP5KL1 overexpressing human cervical cancer HeLa cells. RT-PCR (reverse transcription-polymerase chain reaction) and Western immunoblot analysis were performed to testify the mRNA and protein levels of PIP5KL1 in HeLa cells. The effect of PIP5KL1 overexpression on in vitro cell growth was assessed by measuring cell proliferation and migration. The athymic nude mouse model was used to examine the effects of PIP5KL1 on tumour growth in vivo. Stable transfection of PIP5KL1 induced a significant increase in expression of both mRNA and protein levels and consequent robust inhibition of proliferation (P<0.05) and migration (P<0.05) of HeLa cells. Overexpression of PIP5KL1 significantly suppressed the growth of HeLa xenograft tumours in the flanks of nude mice. Taken together, these studies indicate a functional negative correlation between elevated levels of PIP5KL1 and the development of human cervical cancer, suggesting that PIP5KL1 overexpression may suppress cervical cancer formation.

Overexpression of PIP5KL1 suppresses cell proliferation and migration in human gastric cancer cells.

Phosphatidylinositol-4-phosphate 5-kinase-like 1 (PIP5KL1), the forth member of phosphatidylinositol-4-phosphate 5-kinases (PIPKs) type I, acts as a scaffold for localization and activation of PIPKs, which mediates numerous cellular processes. However, the role of PIP5KL1 in the development of human cancer is still lacking. We therefore examined the expression of PIP5KL1 in human normal and cancer tissues by tissue microarrays (TMAs). Reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence imaging analysis were used to testify the mRNA and protein levels of PIP5KL1 in human gastric cancer cell line (BGC823). The cell proliferation was investigated with 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay. Both wound healing and transwell migration assay were performed to study the cell migration. The phosphorylation of v-akt murine thymoma viral oncogene homolog 1 (AKT1) was determined by western immunoblot analysis. Immunostaining of gastric cancer tissue microarrays revealed a negative correlation between PIP5KL1 overexpression and gastric cancer in situ. Transient transfection PIP5KL1 induced a significant increase expression at both transcriptional and translational levels and consequent robust inhibition of proliferation (P < 0.05) and migration (P < 0.05) of BGC823 cells. Overexpression of PIP5KL1 markedly inhibited (P < 0.05) serum-induced phosphorylation of AKT1. Taken together, these studies indicate a functional negative correlation between elevated levels of PIP5KL1 and the development of human gastric cancer, suggesting that PIP5KL1 overexpression may suppress gastric cancer formation.

Melochia corchorifolia extract inhibits melanogenesis in B16F10 mouse melanoma cells via activation of the ERK signaling.

BACKGROUND: Numerous researches have focused on discovering available inhibitors of melanogenesis from natural medicinal plants with stable efficacy and safety to resolve cutaneous hyperpigmentary problems. Melochia corchorifolia Linn. (MC) has been used as folk medicine to treat various diseases. However, the effect of MC on melanogenesis remains unknown. AIM: In this study, we investigated the effect of MC extract on melanogenesis and its underlying mechanisms in B16F10 mouse melanoma cells. METHODS: B16F10 cells were treated with MC extract, and then, cell viability, melanin content, and tyrosinase activity were analyzed. The mRNA and protein expression of tyrosinase and microphthalmia-associated transcription factor (MITF) were evaluated using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting, respectively. Phosphorylated or total protein levels in MC extract-induced signaling pathways were analyzed by Western blotting. RESULTS: Treatment of B16F10 cells with MC extract inhibited melanin synthesis and intracellular tyrosinase activity in a dose-dependent manner with no cytotoxicity. Protein and mRNA expressions of tyrosinase and MITF were also significantly decreased by MC extract treatment. In addition, phosphorylated level of extracellular signal-regulated kinase (ERK) was obviously increased by MC extract, but AKT pathway was not activated. Inhibited ERK phosphorylation by pretreatment with a selective ERK inhibitor PD98059 significantly reversed the decreased melanin content induced by treatment with MC extract in B16F10 cells. CONCLUSION: MC extract inhibits melanogenesis in B16F10 mouse melanoma cells through suppression of MITF-tyrosinase signaling pathway by ERK activation.

The UbL-UBA Ubiquilin4 protein functions as a tumor suppressor in gastric cancer by p53-dependent and p53-independent regulation of p21.

Ubiquilin4 (Ubqln4), a member of the UbL-UBA protein family, serves as an adaptor in the degradation of specific substrates via the proteasomal pathway. However, the biological function of Ubqln4 remains largely unknown, especially in cancer. Here, we reported that Ubqln4 was downregulated in gastric cancer tissues and functioned as a tumor suppressor by inhibiting gastric cancer cell proliferation in vivo and in vitro. Overexpression of Ubqln4-induced cellular senescence and G1-S cell cycle arrest in gastric cancer cells and activated the p53/p21 axis. Moreover, Ubqln4 regulated p21 through both p53-dependent and p53-independent manners. Ubqln4 interacted with RNF114, an E3 ubiquitin ligase of p21, and negatively regulated its expression level, which in turn stabilized p21 by attenuating proteasomal degradation of p21. These effects of Ubqln4 were partly abrogated in gastric cancer cells upon silencing of p21. Our findings not only establish the anti-tumor potential of Ubqln4 in gastric cancer but also reveal a role for Ubqln4 in regulation of the cell cycle and cellular senescence via stabilizing p21.

Clinicopathological Characteristics and Prognosis of Proximal and Distal Gastric Cancer during 1997-2017 in China National Cancer Center.

BACKGROUND: The prognostic relevance of gastric tumor location has been reported and debated. Our study was conducted to examine the differences in clinicopathological features, prognostic factors, and overall survival (OS) between patients with proximal gastric cancer (PGC) and distal gastric cancer (DGC). PATIENTS AND METHODS: Patients with PGC or DGC were identified from the China National Cancer Center Gastric Cancer Database (NCCGCDB) during 1997-2017. Survival analysis was performed via Kaplan-Meier estimates and Cox proportional hazards models. RESULTS: We reviewed 16,119 cases of gastric cancer patients, including 6,479 of PGC and 9,640 of DGC. PGC patients presented as older patients (61.5 versus 56.4 years, P<0.001) and more males (82.9% versus 68.2%, P<0.001). Compared with DGC, PGC was more likely to be in later pT stage (pT3 and pT4, 65.0% versus 52.8%, P<0.001) and lymph node metastasis (54.8% versus 50.9%, P<0.001). In univariate analysis, PGC patients had a worse survival outcome in stage I (Hazard ratio [HR] = 2.04, 95% CI: 1.42-2.94) but a better prognosis in stage IV (HR = 0.85, 95% CI: 0.73-0.98) when compared to DGC patients. However, multivariate analysis demonstrated that PGC was not an independent predictor for poor survival (HR = 1.07, 95% CI: 1.00-1.14). Results from multivariate analysis also revealed that pT4, lymph node metastasis, distant metastasis, no gastrectomy, and Borrmann IV were independent predictors associated with poor survival for both PGC and DGC patients. Additional prognostic factors for PGC patients included underweight (BMI < 18.5) (HR = 1.29, 95% CI: 1.06-1.58), linitis plastica (HR = 2.13, 95% CI: 1.25-3.65), and overweight (23 ≤ BMI <27.5) (HR = 0.80, 95% CI: 0.71-0.90). During the 20-year study period, the 5-year OS increased significantly for both PGC and DGC, with the increase rate of 91.7% and 67.7%, respectively. CONCLUSION: In China, PGC significantly differed from DGC in clinicopathological characteristics and prognostic factors. However, there was no significant relationship between survival outcome and gastric tumor location.

CYP2A6 Polymorphisms Associate with Outcomes of S-1 Plus Oxaliplatin Chemotherapy in Chinese Gastric Cancer Patients.

Gastric carcinoma is a heterogeneous malignant disease involving genetic factors. To identify predictive markers for gastric cancer treatment in Chinese patients, we evaluated the association between polymorphisms of the gene encoding cytochrome P450 2A6 (CYP2A6) and outcomes of S-1 plus oxaliplatin (SOX) chemotherapy treatment. Clinical data on 60 consecutive gastric cancer patients receiving SOX regimen were collected prospectively. We sequenced all exons of CYP2A6 and a total of 22 different polymorphisms were detected in the present study. Comprehensive analyses of these genetic polymorphisms were performed to determine their association with both safety and efficacy of SOX regimen. Our results showed that polymorphisms of CYP2A6 were associated with the safety and efficacy of SOX treatment. Among them, missense mutations CYP2A6 rs60823196 and rs138978736 could be possible risk factors (P<0.05) for severe diarrhea induced by SOX, whereas CYP2A6 rs138978736 could be a conceivable predictor for overall survival of patients treated with SOX adjuvant chemotherapy. Further large-scale randomized prospective studies are warranted to confirm these findings.