Long noncoding RNA EPB41L4A-AS1 functions as an oncogene by regulating the Rho/ROCK pathway in colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignant tumors worldwide. In terms of cancer-related death, colon cancer ranks second and third among men and women, respectively, and the incidence is increasing annually. Accumulating evidence have indicated that long noncoding RNA (lncRNA) plays an important role in tumorigenesis. In this study, we found that lncRNA EPB41L4A-AS1 was highly expressed in CRC tissues and was associated with poor prognosis and tumor metastasis in patients with CRC. In vitro studies showed that the knockdown of EPB41L4A-AS1 inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition of CRC cells. Mechanically, we found that EPB41L4A-AS1 may participate in the development of CRC by activating the Rho/Rho-associated protein kinase signaling pathway. Collectively, these results demonstrated that EPB41L4A-AS1 can promote the proliferation, invasion, and migration of CRC, and it may be a novel biomarker for the diagnosis and targeted treatment of CRC.

NF-κB-induced WIP1 expression promotes colorectal cancer cell proliferation through mTOR signaling.

Colorectal cancer (CRC) is one of the major causes of cancer deaths worldwide. Wild-type p53-induced protein 1 (WIP1) is overexpressed in multiple human cancers and acted as an oncogene. This study was aimed to investigate the effect of WIP1 in colorectal cancer growth and analyzed underlying mechanisms. Herein, we determined WIP1 expression in CRC tissues and cell lines, as well as evaluated its detailed function in CRC cell proliferation. Several factors have been reported to mediate WIP1 effects; herein, we examined the involvement of mTOR and p21 in WIP1 regulation of CRC cell proliferation. Moreover, NF-κB has been regarded as a positive transcriptional regulator of WIP1 to activate its expression. NF-κB knockdown suppressed CRC cell proliferation, which could be reversed by WIP1 overexpression, through p21 and mTOR. Further, we examined the binding of NF-κB to the promoter region of WIP1. In CRC tissues, NF-κB expression was significantly up-regulated, and positively correlated with WIP1 expression, suggesting that inhibiting NF-κB expression to attenuate its activating effect on WIP1 expression presented a promising strategy of controlling excess proliferation of CRC cell. In summary, WIP1 promotes CRC proliferation through p21 and mTOR, both downstream targets of p53; NF-κB served as a positive transcriptional regulator of WIP1 to activate its expression and affect its function in CRC cells. Our finding provided a novel strategy for treatment for CRC.

Curcumin activates DNA repair pathway in bone marrow to improve carboplatin-induced myelosuppression.

Carboplatin, a second-generation platinum agent, has been used as a cancer therapy for decades and exhibits strong anti-tumor activity. However, the wide application of carboplatin is largely limited due to its side effects, especially myelosuppression. Here, we combined carboplatin with curcumin, a natural product that improves tumor-induced anemia, for the treatment of fibrosarcoma to improve the side effects of carboplatin. We first examined the synergistic and attenuated effects of the two agents in a T241-bearing mouse model. The combination therapy caused no obvious synergistic effect, but curcumin significantly improved the survival rate of carboplatin-treated mice. Histologic analysis of the kidney and bone marrow revealed that curcumin improved carboplatin-induced myelosuppression but did not affect the kidney. To determine the mechanism involved, we introduced a probe derived from curcumin to identify its targets in bone marrow cells and the results provided us a clue that curcumin might affect the DNA repair pathway. Western blot analysis revealed that curcumin up-regulated BRCA1, BRCA2 and ERCC1 expression in bone marrow. In conclusion, curcumin attenuates carboplatin-induced myelosuppression by activating the DNA repair pathway in bone marrow cells.

Curcumol potentiates celecoxib-induced growth inhibition and apoptosis in human non-small cell lung cancer.

Combinatorial therapies that target multiple signaling pathways may provide improved therapeutic responses over monotherapies. Celecoxib and curcumol are two highly hydrophobic drugs which show bioavailability problems due to their poor aqueous solubility. In the present study, we evaluated the effects of celecoxib and curcumol alone and in combination on cell proliferation, invasion, migration, cell cycle and apoptosis induction in non-small cell lung cancer (NSCLC) cells using in vitro and in vivo experiments. Our data showed that the sensitivity of a combined therapy using low concentration of celecoxib and curcumol was higher than that of celecoxib or curcumol alone. Suppression of NF-κB transcriptional activity, activation of caspase-9/caspase-3, cell cycle G1 arrest, and inhibition of survival MAPK and PI3K/AKT signaling pathway contributed to the synergistic effects of this combination therapy for induction of apoptosis. Additionally, either celecoxib alone or in combination with curcumol inhibited NSCLC cell migration and invasion by suppressing FAK and matrix metalloproteinase-9 activities. Furthermore, the combined treatment reduced tumor volume and weight in xenograft mouse model, and significantly decreased tumor metastasis nodules in lung tissues by tail vein injection. Our results confirm and provide mechanistic insights into the prominent anti-proliferative activities of celecoxib and/or curcumol on NSCLC cells, which provide a rationale for further detailed preclinical and potentially clinical studies of this combination for the therapy of lung cancer.

Curcumin inhibits angiogenesis and improves defective hematopoiesis induced by tumor-derived VEGF in tumor model through modulating VEGF-VEGFR2 signaling pathway.

Curcumin, a natural polyphenol compound from the perennial herb Curcuma longa, has been proved to be beneficial for tumor-bearing animals through inhibiting tumor neovasculature formation, but the underlying mechanisms are unclear. Here, we aim to test whether curcumin affects VEGF-VEGFR2 signaling pathway and attenuates defective hematopoiesis induced by VEGF in tumor model. We demonstrated that curcumin inhibited proliferation, migration of HUVEC under VEGF stimulation and caused HUVEC apoptosis, and blocked VEGFR2 activation and its downstream signaling pathways in vitro. Furthermore, in VEGF over-expressing tumor model, curcumin significantly inhibited the tumor growth accelerated by VEGF in a dose-dependent manner and improved anemia and extramedullary hematopoiesis in livers and spleens of tumor-bearing mice induced by tumor-derived VEGF. Immunohistochemical analysis showed that curcumin normalized vasculature structures of livers and reduced tumor microvessel density. ELISA revealed that curcumin suppressed VEGF secretion from tumor cells both in vitro and in vivo. Survival analysis showed that curcumin significantly improved survival ability of VEGF tumor-bearing mice. Taken together, these findings establish curcumin as a modulator of VEGF and VEGF-VEGFR2 signaling pathway, with potential implication for improving the quality of life of cancer patients.

Endostar attenuates melanoma tumor growth via its interruption of b-FGF mediated angiogenesis.

To develop optimal therapeutics is one of the hotspots in both clinical and basic melanoma studies. Previous studies indicate that fibroblast growth factors (b-FGF/FGF-2), an angiogenesis inducer beyond VEGF, might be a potential drug target in melanoma. As a novel anti-angiogenesis peptide drug, Endostar has shown promising therapeutic efficacy in non-small cell lung cancer. However, the effect of Endostar on b-FGF-induced angiogenesis in melanoma is unraveled. To this end, both in vivo and in vitro experiments were conducted and it was found that treatment of Endostar could inhibit tumor growth, which was accompanied by decreased micro-vessel density and serum b-FGF levels in a mouse melanoma model. In addition, treatment with Endostar in blood vessel endothelial cells could reduce their proliferation, cell migration and tube formation capacity in a dosage-dependent manner. Moreover, treatment of Endostar could also attenuate b-FGF-activated phosphorylation of p38 and ERK1/2 in HUVECs. These findings indicate that Endostar might exert its anti-tumor effect via suppressing b-FGF-induced angiogenesis and b-FGF-activated MAPK signaling pathway, suggesting that Endostar might be a potential choice for clinical melanoma treatment.

Expression and characterization of Momordica Chanrantia anti-hyperglycaemic peptide in Escherichia coli.

A nucleic acid sequence MC, encoding Momordica Chanrantia anti-hyperglycaemic peptide MC6 (accession: AAX06814) synthesized according to Escherichia coli preferred codons, was cloned and expressed in E. coli. Recombinant protein pQE8-MC (about 3.5 kDa) was purified and analyzed by 20% SDS-PAGE and western blot. It revealed that the expressed pQE8-MC had good solubility in aqueous media. An HPLC assay was used to confirm the expression of pQE8-MC. Subsequent pharmacological activity assay revealed a significant hypoglycemic effect of low dose treatments of pQE8-MC on male kunming mice. Four hours after an intravenous tail injection, the blood sugar levels of mice treated with pQE8-MC saline solution A3 (1 mg/kg BW) decreased greatly (P < 0.01) relative to the levels of a control group. This suggests that pQE8-MC, expressed in bioengineered E. coli, has a similar hypoglycemic function to the natural protein MC6 from M. Chanrantia. These results reveal the possibility of using bio-engineered bacteria as an anti-diabetic agent.