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Background To date, anatomic tumor length is a key criterion for cancer staging and can be used to evaluate the effectiveness of therapies. This article describes growth pattern that can be used as a new characteristic to represent disease burden and tumor features and predict lymphatic metastasis. Methods Patients with breast cancer were included in this 10-year (1999–2008) hospital-based multicenter retrospective study. The pathologic length/height ratio was used to illustrate the correlation between tumor features, behaviors and treatments in breast malignancies. The most appropriate ratio was chosen based on the comprehensive evaluation of p value and changing trend of each characteristic. Results The sample consisted of 4211 women diagnosed with breast cancer. Among them, 2037 patients with complete pathologic length, width and height information were included in the final analysis. There were 2.34 ± 4.77 metastatic lymph nodes for spheroid tumors and 3.21 ± 5.82 for ellipsoid tumors when the cutoff point was 2. In addition, the proportion of ellipsoidal tumors gradually increased from 54.36 to 56.67% in the upper outer quadrant (UOQ) and from 6.7 to 9.03% in the central region with an increase in the cutoff point. The proportion of ER + PR + ellipsoid tumors significantly decreased from 50.1 to 45.35% and that of ER–PR ellipsoid tumors significantly increased from 32.73 to 36.24% with an increase in the cutoff point. Additionally, the best length/weight ratio to distinguish spheroid and ellipsoid tumors was 2. Conclusion This study described for the first time how growth pattern is correlated with tumor malignancy and how it influences the selection of therapeutic strategies for patients.

Background The homeobox gene family, encoding a specific nuclear protein, is essential for embryonic development, differentiation, and homeostasis. The role of the HOXB3 protein varies in different tumors. This study aims to explore the role of the HOXB3 gene in breast cancer. Method Differentially expressed genes were screened by analyzing metastatic breast cancer gene chip data from TCGA and GEO databases. The function of the selected HOXB3 gene was also analyzed in different databases and through molecular biology methods, such as qRT-PCR, western blot and IF to verify bioinformatics findings. Results Both bioinformatics analyses and western blot showed that HOXB3 was lost in breast cancer compared to normal breast tissue. Survival analysis also showed that lower expression of HOXB3 was associated with poor prognosis. Bioinformatics analyses further showed that HOXB3 was positively correlated with hormone receptors. Metascape for GO analysis of GEO data provided possible mechanisms that HOXB3 could positively regulate cell adhesion, inhibit cell proliferation and activate immune response in breast cancer; moreover, GSEA included several cancer-associated pathways. Conclusion In summary, HOXB3 expression was decreased in breast cancer, and it was associated with poor prognosis. It might become a new biomarker to predict prognosis of breast cancer.

ATP-binding cassette sub-family G member 2 (ABCG2) confers to the major phenotypes of side population (SP) cells, the cancer stem-like cells. In this study, the SP cells displayed a distinctly higher ABCG2 expression level, sphere formation efficiency (SFE) and growth rate even under hypoxia condition. CXCR4 overexpression by pcDNA-CXCR4 transfection robustly increased ABCG2 expression, and promoted SFE and growth of hypoxic SP cells, while CXCR4 inhibitor AMD3100 could suppress the promotion. Additionally, we found that CXCR4 promoted the expression of c-Jun, a major gene in the oncogenic JNK/c-Jun pathway. Our data on electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays both showed that c-Jun directly bound with the ABCG2 promoter sequence. Moreover, overexpression of JNK/c-Jun promoted ABCG2 expression, SFE, and growth of hypoxic SP cells and the promotion could be rescued by c-Jun inhibitor SP600125. In conclusion, CXCR4 increases the growth and SFE of breast cancer SP cells under hypoxia through c-Jun-mediated transcriptional activation of ABCG2.

Even though early detection methods and treatment options are greatly improved, chemoresistance is still a tremendous challenge for breast cancer therapy. Breast cancer stem cells (BCSCs) represent a subpopulation that is central to chemoresistance. We aim to investigate the relationship between SLC34A2 and chemoresistance in BCSCs and identify the underlying mechanisms by which SLC34A2 regulates chemoresistance in BCSCs. Fluorescence Activated Cell Sorting (FACS) analysis showed the presence of a variable fraction of CD44(+)CD24(-) cells in 25 out of 25 breast cancer samples. We cultured primary breast cancer sample cells and breast cancer cell line cells to induce sphere formation in serum-free medium. Following sorting of CD44(+)CD24(-) cells from spheres, we showed that CD44(+)CD24(-) cells displayed stem cell-like features and were resistant to chemotherapy drug doxorubicin. Significantly, enhanced SLC34A2 expression correlated with chemoresponse and survival of breast cancer patients. We subsequently indicated that increased SLC34A2 expression in BCSCs directly contributed to their chemoresistance by a series of in vitro and in vivo experiments. Furthermore, we demonstrated that SLC34A2 induced chemoresistance in BCSCs via SLC34A2-Bmi1-ABCC5 signaling. Finally, we showed that ABCC5 was a direct transcriptional target of Bmi1 by chromatin immunoprecipitation (ChIP). In conclusion, our work indicated that decreased SLC34A2 expression sensitized BCSCs to doxorubicin via SLC34A2-Bmi1-ABCC5 signaling and shed new light on understanding the mechanism of chemoresistance in BCSCs. This study not only bridges the missing link between stem cell-related transcription factor (Bmi1) and ABC transporter (ABCC5) but also contributes to development of potential therapeutics against breast cancer.

Ginsenoside Rh2 (G-Rh2), a component extracted from roots of ginseng, exhibited anti-cancer pharmacological activities by inhibiting proliferation and inducing apoptosis in lung cancer cells. However, the mechanisms of G-Rh2 suppressing lung cancer development remained elusive. This study tried to investigate the possible mechanism involved in anti-proliferative effect of G-Rh2 in lung cancer cells. As results, G-Rh2 inhibited the proliferation of H1299 cells in a dose-dependent manner by inducing cell apoptosis. Activating transcription factor 4 (ATF4), CCAAT/enhancer-binding protein homologous protein (CHOP), and caspase-4 were involved in G-Rh2-induced apoptosis of H1299 cells. It was also found that G-Rh2 could up-regulate expressions of ATF4, CHOP and caspase-4 in H1299 cells in a dose-dependent manner. In addition, NAC (N-acetylcysteine, a reactive oxygen species (ROS) scavenger) treatment dramatically decreased ROS generation in H1299 cells; both of NAC and 4-PBA (4-phenylbutyrate, a specific endoplasmic reticulum (ER) stress inhibitor) administration impaired apoptosis and expression levels of ATF4, CHOP and caspase-4 in G-Rh2 incubated H1299 cells. In vivo assays extended the significance of these results, showing that G-Rh2 inhibited lung cancer growth and the inhibition effects of G-Rh2 in tumor growth were significantly reduced by inhibition of ER stress. In conclusion, G-Rh2 inhibited proliferation of H1299 cells by inducing ROS mediated ER stress dependent cell apoptosis.

Background: Protease serine 8 (PRSS8), a trypsin-like serine peptidase, has been shown to function as a tumour suppressor in various malignancies. The present study aimed to investigate the expression pattern, prognostic value and the biological role of PRSS8 in human hepatocellular carcinoma (HCC). Methods: PRSS8 expression in 106 HCC surgical specimens was examined by Real-time polymerase chain reaction (PCR) and immunohistochemistry, and its clinical significance was analysed. The role of PRSS8 in cell proliferation, apoptosis and invasion were examined in vitro and in vivo. Results: PRSS8 mRNA and protein expression were decreased in most HCC tumours from that in matched adjacent non-tumour tissues. Low intratumoral PRSS8 expression was significantly correlated with poor overall survival (OS) in patients with HCC (P = 0.001). PRSS8 expression was an independent prognostic factor for OS (hazard ratio [HR] = 1.704, P = 0.009). Furthermore, restoring PRSS8 expression in high metastatic HCCLM3 cells significantly inhibited cell proliferation and invasion. In contrast, silencing PRSS8 expression in non-metastatic HepG2 cells significantly enhanced cell growth and invasion. Moreover, our in vivo data revealed that attenuated PRSS8 expression in HepG2 cells greatly promoted tumour growth, while overexpression of PRSS8 remarkably inhibited tumour growth in an HCCLM3 xenograft model. Enhanced cell growth and invasion ability mediated by the loss of PRSS8 expression was associated with downregulation of PTEN, Bax and E-cadherin and an upregulation in Bcl-2, MMP9 and N-cadherin. Conclusions: Our data demonstrate that PRSS8 may serve as a tumour suppressor in HCC progression, and represent a valuable prognostic marker and potential therapeutic target for HCC.

Background Interleukin-37 (IL-37), a newly identified member of the IL-1 family, has been known to play an immunosuppressive role in a variety of inflammatory disorders, but whether it participates in the regulation of pathogenesis of non-small cell lung cancer (NSCLC) has not been investigated. Methods Real-time polymerase chain reaction (PCR), western blotting, and immunohistochemical staining were employed to detect IL-37 expression in NSCLC tissues and corresponding adjacent tissues. The correlations between IL-37 expression and clinicopathological characteristics, prognosis were analyzed. Stable clone with overexpression of IL-37 was generated in H1299 cell lines. Cell growth, cell cycle and cell apoptosis assays were carried out for detecting proliferation and apoptosis of H1299 cells. The effects of IL-37 on NSCLC progression in vivo was performed in a xenografted lung tumor model in nude mice. The concentrations of IL-37 and VEGF in the s growth medium supernatants were quantified by ELISA. The antiangiogenic effect of IL-37 on HUVEC was measured by tube formation assay. Results IL-37 mRNA and protein expressions were significantly decreased in NSCLC tissues, and decreased intratumoral IL-37 expression was significantly associated with tumor state, TNM stage and poor prognosis in NSCLC patients. In addition, intratumoral IL-37 expression was an independent prognostic factors for Overall survival (hazard ratio = 2.047; P = 0.011). Overexpression of IL-37 exerted no direct effect on cell proliferation and apoptosis of H1299 lung cancer cells in vitro, but significantly inhibited tumor growth in a H1299 xenograft model in vivo. Furthermore, there was no significant change in immune cell infiltration in IL-37 over-expressing tumors; instead, we found decreased microvessel density (MVD) and VEGF levels in IL-37-expressing tumors. Additional studies showed IL-37 could directly inhibit HUVEC cells growth and capillary structure formation. Finally, we found that decreased IL-37 expression was associated with high MVD in NSCLC patients. Conclusions Our findings demonstrate a protective role for IL-37 in lung cancer development, possibly through inhibiting tumor angiogenesis. IL-37 could serve as a promising therapeutic target for NSCLC. Electronic supplementary material The online version of this article (doi:10.1186/s13046-016-0293-3) contains supplementary material, which is available to authorized users.

Reducingβamyloid- (Aβ-) induced microglial activation is believed to be effective in treating Alzheimer’s disease (AD). Microglia can be activated into classic activated state (M1 state) or alternative activated state (M2 state), and the former is harmful; in contrast, the latter is beneficial. Gypenoside (GP) is the major bioactive constituent ofGynostemma pentaphyllum, a traditional Chinese herb medicine. In this study, we hypothesized that GP attenuates Aβ-induced microglial activation by ameliorating microglial M1/M2 states, and the process may be mediated by suppressor of cell signaling protein 1 (SOCS1). In this study, we found that Aβexposure increased the levels of microglial M1 markers, including iNOS expression, tumor necrosis factorα(TNF-α), interleukin 1β(IL-1β), and IL-6 releases, and coadministration of GP reversed the increase of M1 markers and enhanced the levels of M2 markers, including arginase-1 (Arg-1) expression, IL-10, brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF) releases in the Aβ-treated microglial cells. SOCS1-siRNA, however, significantly abolished the GP-induced effects on the levels of microglial M1 and M2 markers. These findings indicated that GP attenuates Aβ-induced microglial activation by ameliorating M1/M2 states, and the process may be mediated by SOCS1.

Epithelial ovarian cancer (EOC) accounts for 90% of all ovarian cancer, which is the third most common gynaecological malignancy worldwide. Dysregulation of miRNAs is involved in the development of different types of EOC. The present study was designed to investigate the role of abnormal expression of miR-215 in the development of EOC and to elucidate the possible molecular mechanisms. mRNA expression of miR-215 was significantly decreased in EOC tissues and cell lines. Upregulation of miR-215 inhibited cell proliferation, promoted apoptosis and increased sensitivity to chemotherapy drugs in EOC cells. In contrast, downregulation of miR-215 increased cell proliferation, inhibited apoptosis and decreased sensitivity to chemotherapy drugs in EOC cells. In addition, the X-chromosome-linked inhibitor of apoptosis (XIAP) expression was significantly increased in EOC tissues and cell lines. Downregulation of XIAP inhibited cell proliferation, promoted apoptosis and increased sensitivity to chemotherapy drugs in EOC cells. Upregulation of miR-215 notably inhibited the expression of XIAP. Moreover, overexpression of XIAP significantly inhibited miR-215-exerted decrease of proliferation, increase of apoptosis and increase of sensitivity to chemotherapy drugs. In conclusion, we identified miR-215 as a potential tumor suppressor in patients with EOC downregulating expression of the oncogenic regulator XIAP. The data demonstrate that miR-215/XIAP pathway may serve as novel therapeutic targets and prognostic markers in patients with EOC.