Preliminary study on the inhibitory effect of tumor suppressor gene KPC1 on the proliferation in gastric carcinoma cell.

BACKGROUND: To investigate Kip1 ubiquitination-promoting complex 1 (KPC1) expression and its relationship with NF-κB p50 in gastric cancer cell lines. METHODS: The expression of KPC1 and NF-κB p50 in tissue samples from 159 gastric cancer patients after tumor resection and normal gastric mucosa samples from 56 patients as negative controls was retrospectively studied. The relationship between KPC1, NF-κB p50, and clinicopathological factors was analyzed, and the correlation between KPC1 and cytoplasmic NF-κB p50 was determined. The expression level of KPC1 and NF-κB p50 was researched using reverse transcription (RT) polymerase chain reaction (RT-PCR) and Western blotting in 3 differentiated human gastric cancer cell lines (AGS, SGC-7901 and MGC-803). RESULTS: Immunohistochemistry indicated that KPC1 and NF-κB p50 expression was significantly decreased in gastric cancer cases, and the level of expression varied across the differentiated gastric cancer tissues. KPC1 and NF-κB p50 expression was significantly connected with tumor differentiation, tumor-node-metastasis (TNM) staging, and metastasis of 159 patients suffering from gastric cancer (P<0.05), but not correlated with age and lesion size (P>0.05). KPC1 was positively connected with the expression of NF-κB p50 by the Spearman correlation analysis (r=0.427, P<0.05). The expression of KPC1 and NF-κB p50 mRNA was reduced, and there were differences in the 3 differentiated human gastric cancer cell lines, as confirmed by western blotting. CONCLUSIONS: The co-expression of KPC1 and cytoplasmic NF-κB p50 in gastric cancer promotes tumor suppressor gene expression. Therefore, limiting the growth of tumor cells may inhibit the development of gastric cancer.

Effect of photodynamic therapy with (17R,18R)-2-(1-hexyloxyethyl)-2-devinyl chlorine E6 trisodium salt on pancreatic cancer cells in vitro and in vivo.

AIM: To investigate the antitumor effects and underlying mechanisms of (17R,18R)-2-(1-hexyloxyethyl)-2-devinyl chlorine E6 trisodium salt (YLG-1)-induced photodynamic therapy (PDT) on pancreatic cancer in vitro and in vivo. METHODS: YLG-1 is a novel photosensitizer extracted from spirulina. Its phototoxicity, cellular uptake and localization, as well as its effect on reactive oxygen species (ROS) production, apoptosis, and expression of apoptosis-associated proteins were detected in vitro. An in vivo imaging system (IVIS), the Lumina K imaging system, and mouse models of subcutaneous Panc-1-bearing tumors were exploited to evaluate the drug delivery pathway and pancreatic cancer growth in vivo. RESULTS: YLG-1 was localized to the mitochondria, and the appropriate incubation time was 6 h. Under 650 nm light irradiation, YLG-1-PDT exerted a potent cytotoxic effect on pancreatic cancer cells in vitro, which could be abolished by the ROS scavenger N-acetyl-L-cysteine (NAC). The death mode caused by YLG-1-PDT was apoptosis, accompanied by upregulated Bax and cleaved Caspase-3 and decreased Bcl-2 expression. The results from the IVIS images suggested that the optimal administration route was intratumoral (IT) injection and that the best time to conduct YLG-1-PDT was 2 h post-IT injection. Consistent with the results in vitro, YLG-1-PDT showed great growth inhibition effects on pancreatic cancer cells in a mouse model. CONCLUSION: YLG-1 is a potential photosensitizer for pancreatic cancer PDT via IT injection, the mechanisms of which are associated with inducing ROS and promoting apoptosis.

Biodistribution and toxicity assessment of intratumorally injected arginine-glycine-aspartic acid peptide conjugated to CdSe/ZnS quantum dots in mice bearing pancreatic neoplasm.

Quantum dots (QDs) conjugated with arginine-glycine-aspartic acid (RGD) peptides (which are integrin antagonists) are novel nanomaterials with the unique optical property of high molar extinction coefficient, and they have potential utility as photosensitizers in photodynamic therapy (PDT). Our group previously demonstrated significant benefits of using PDT with QD-RGD on pancreatic tumor cells. This study aimed to evaluate the biodistribution and toxicity of QD-RGD in mice prior to in vivo application. Mice with pancreatic neoplasms were intratumorally injected with varying doses of QD-RGD, and the biodistribution 0-24 h post injection was compared to that in control mice (intravenously injected with unconjugated QD). Various tissue samples were collected for toxicity analyses, which included inductively coupled plasma mass spectrometry (ICP-MS) to assess Cd2+ concentrations and hematoxylin-eosin staining for histopathological examination. Fluorescent imaging revealed relatively sufficient radiant efficiency in mice under specific conditions. The ICP-MS and HE data showed no significant signs of necrosis due to Cd2+ release by QDs. The mice survived well and had no apparent weakness or weight loss during the 4 weeks post injection. These findings provide novel insights into the biodistribution of QD-RGD and encourage profound in vivo studies regardless of safety concerns. These findings alleviate safety concerns and provide novel insights into the biodistribution of QD-RGD, offering a solid foundation for comprehensive in vivo studies.

TM4SF1 Promotes Metastasis of Pancreatic Cancer via Regulating the Expression of DDR1.

Transmembrane-4-L-six-family-1(TM4SF1), a four-transmembrane L6 family member, is highly expressed in various pancreatic cancer cell lines and promotes cancer cells metastasis. However, the TM4SF1-associated signaling network in metastasis remains unknown. In the present study, we found that TM4SF1 affected the formation and function of invadopodia. Silencing of TM4SF1 reduced the expression of DDR1 significantly in PANC-1 and AsPC-1 cells. Through double fluorescence immuno-staining and Co-immunoprecipitation, we also found that TM4SF1 colocalized with DDR1 and had an interaction with DDR1. In addition, upregulating the expression of DDR1 rescued the inhibitory effects of cell migration and invasion, the expression of MMP2 and MMP9 and the formation and function of invadopodia when TM4SF1 silenced. In pancreatic cancer tissues, qRT-PCR and scatter plots analysis further determined that TM4SF1 had a correlation with DDR1. Collectively, our study provides a novel regulatory pathway involving TM4SF1, DDR1, MMP2 and MMP9, which promotes the formation and function of invadopodia to support cell migration and invasion in pancreatic cancer.

Effects of arginine-glycine-aspartic acid peptide-conjugated quantum dots-induced photodynamic therapy on pancreatic carcinoma in vivo.

Quantum dots (QDs) conjugated with integrin antagonist arginine-glycine-aspartic acid (RGD) peptides (QDs-RGD) are novel nanomaterials with a unique optical property: a high molar extinction coefficient. Previously, we have shown that QDs-RGD demonstrate a photodynamic therapy (PDT) effect as new photosensitizers for the pancreatic cancer cell line SW1990 in vitro. Here, we investigate the application of QDs-RGD in mice bearing pancreatic tumors using PDT. To ensure that more photosensitizers accumulated in tumors, QDs-RGD were injected intratumorally. After selection of an adequate dosage for injection from analyses of biodistribution images captured by an IVIS system, PDT was initiated. Three groups were created according to different PDT procedures. In group 1, mice were injected with QDs-RGD intratumorally, and an optical fiber connected to a laser light was inserted directly into the tumor. Irradiation was sustained for 20 min with a laser light (630 nm) at 100 mW/cm2. In group 2, the laser optical fiber was placed around, and not inserted into, tumors. In group 3, PDT was conducted as in group 1 but without injection of QDs-RGD. After 28 days of observation, tumors on the back of mice in group 1 grew slowly (V/V0 =3.24±0.70) compared with the control groups, whose tumors grew quickly, and the mean V/V0 reached 6.08±0.50 (group 2) and 7.25±0.82 (group 3). Histology of tumor tissues showed more necrotic tissues, more inflammatory cells, and less vascular tissue in the PDT group than those in the control groups. These results suggest that QDs-RGD-mediated PDT, with illumination using an optical fiber inserted directly into the tumor, can inhibit the growth of SW1990 tumors with high efficiency in nude mice.