NUP43 promotes PD-L1/nPD-L1/PD-L1 feedback loop via TM4SF1/JAK/STAT3 pathway in colorectal cancer progression and metastatsis.

Programmed cell death-ligand 1 (PD-L1) has a significant role in tumor progression and metastasis, facilitating tumor cell evasion from immune surveillance. PD-L1 can be detected in the tumor cell nucleus and exert an oncogenic effect by nuclear translocation. Colorectal cancer (CRC) progression and liver metastasis (CCLM) are among the most lethal diseases worldwide, but the mechanism of PD-L1 nuclear translocation in CRC and CCLM remains to be fully understood. In this study, using CRISPR-Cas9-based genome-wide screening combined with RNA-seq, we found that the oncogenic factor NUP43 impacted the process of PD-L1 nuclear translocation by regulating the expression level of the PD-L1 chaperone protein IPO5. Subsequent investigation revealed that this process could stimulate the expression of tumor-promoting factor TM4SF1 and further activate the JAK/STAT3 signaling pathway, which ultimately enhanced the transcription of PD-L1, thus establishing a PD-L1-nPD-L1-PD-L1 feedback loop that ultimately promoted CRC progression and CCLM. In conclusion, our study reveals a novel role for nPD-L1 in CRC, identifies the PD-L1-nPD-L1-PD-L1 feedback loop in CRC, and provides a therapeutic strategy for CRC patients.

LncRNA LUCAT1 contributes to cell proliferation and migration in human pancreatic ductal adenocarcinoma via sponging miR-539.

Pancreatic ductal adenocarcinoma is one of the most aggressive and dreadful malignancies worldwide. Long noncoding RNAs (lncRNAs) have emerged as vital regulators in the development of human malignancies and other disorders. This study aimed to characterize the role of lncRNA lung cancer-associated transcript 1 (lncRNA LUCAT1), a novel cancer-related lncRNA, in human PDAC. Here we initially analyzed the expression patterns of lncRNA LUCAT1 and evaluated its clinical significance. The qRT-PCR analysis and in situ hybridization staining showed that lncRNA LUCAT1 expression was significantly increased in tumorous tissues compared with adjacent normal tissues. Additionally, we found that increased lncRNA LUCAT1 expression was linked to larger tumor size and lymphatic invasion. Consistently, lncRNA LUCAT1 was remarkably up-regulated in PDAC cell lines. To better understand the biological role of lncRNA LUCAT1, we evaluated the effects of lncRNA LUCAT1 knockdown on PDAC cell proliferation, cell cycle progression, migration, and invasion using MTT assays, flow cytometry, Transwell migration, and invasion assays, respectively. Functional studies demonstrated that lncRNA LUCAT1 knockdown dramatically suppressed PDAC cell proliferation, induced cell cycle arrest and inhibited cell migration and invasion. Tumor xenograft in vivo assays displayed that lncRNA LUCAT1 inhibited tumorigenecity of PDAC cells. Mechanistic studies uncovered that lncRNA LUCAT1 acted as a molecular sponge of miR-539 and that miR-539 mediated the effects of lncRNA LUCAT1 on PDAC cell proliferation, cell cycle progression, and motility. Collectively, our findings may offer some novel insights into understanding lncRNA LUCAT1 in PDAC.

Prevention of cancer cachexia by pyrrolidine dithiocarbamate (PDTC) in colon 26 tumor-bearing mice.

BACKGROUND: The precise mechanism of cancer cachexia is not fully elucidated. This study was aimed to assess the effect of pyrrolidine dithiocarbamate (PDTC, an inhibitor of NFkappaB) on interleukin (IL)-6 synthesis and cachexia in colon 26 tumor-bearing mice. METHODS: Murine colon 26 adenocarcinoma cells were inoculated subcutaneously in male BALB/c mice to induce cachexia. Saline and various doses of PDTC (10, 50, or 100 mg/kg/d) were given intraperitoneally daily from 7 days after tumor inoculation to killing. Body weight, food intake, and tumor volume were monitored daily. Serum and tumor tissue levels of IL-6, serum biochemical indicator, and activity of NFkappaB in tumor tissue were investigated in all mice. RESULTS: Significant tissue wasting was observed in all tumor-bearing mice. By day 16, carcass weights of untreated tumor-bearing mice were about 71.3% of healthy controls (p < .01), and the weights of gastrocnemius muscle and epididymal fat were lowered by 42.4% and 70.4% (p < .01), respectively. Furthermore, tumor-bearing caused a significant decrease of serum albumin, glucose, and triglyceride (p < .01) and increase of IL-6 (p < .01) in serum and tumor tissues. Administration of PDTC dose dependently inhibited the NFkappaB activation in tumor tissues, inhibited IL-6 synthesis of the tumor cells, and attenuated the wasting of carcass weight, gastrocnemius muscle, and epididymal fat. Tumor growth was inhibited by PDTC with 100 mg/kg (p < .05). No differences of food intake were found between groups (p > .05). CONCLUSIONS: These results suggest that PDTC, an inhibitor of NFkappaB, can attenuate the development of cachexia in colon 26 tumor-bearing mice through inhibition of IL-6 synthesis regulated by NFkappaB.

[The safety and efficiency of fast track surgery in gastric cancer patients undergoing D2 gastrectomy].

OBJECTIVE: To investigate the safety and efficacy of fast track surgery (FTS) management in gastric cancer undergoing D2 gastrectomy. METHODS: Eighty gastric cancer patients undergoing D2 gastrectomy were recruited prospectively. Patients were assigned to receive FTS management (n = 40) or conventional perioperative care (n = 40). The FTS care included shorten preoperative fasting time, no nasogastric decompressing tubes and abdominal drainage placed, early postoperative oral feeding, multimodal analgesia, and early mobilisation. The length of postoperative hospital stay, medical cost, nutritional status, gut function, and postoperative complications in the two groups were recorded and compared. RESULTS: FTS group was associated with a significantly shorter postoperative hospital stay compared with conventional care group [(5.6 +/- 1.3) d vs. (9.4 +/- 1.9) d, P < 0.05]. Medical cost was less [(18 620 +/- 2360) Yuan vs. (20 370 +/- 2440) Yuan, P < 0.05] and duration of intravenous infusion [(3.5 +/- 1.4) d vs. (5.8 +/- 1.9) d, P < 0.05] was also shorter. First passage of flatus was earlier in FTS group than in conventional care group [(4.3 +/- 0.4) d vs. (5.5 +/- 0.9) d, P < 0.05]. Loss of body weight in the postoperative period was less in FTS group [(3.2 +/- 0.8) kg vs. (4.3 +/- 1.6) kg, P < 0.05]. There was no difference in morbidity or mortality between the two groups. CONCLUSION: FTS in D2 gastrectomy is safe and efficient, and it can shorten postoperative hospital stay and hasten return of gut function.

Change of the growth hormone-insulin-like growth factor-I axis in patients with gastrointestinal cancer: related to tumour type and nutritional status.

Changes in the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis, especially acquired GH resistance, develop in many severe illnesses, including cachexia. To study changes in the GH-IGF-I axis in patients with cancer cachexia, biochemical markers and body composition parameters were measured in eighty-eight gastric cancer patients, thirty colorectal cancer patients (subclassified according to the presence or absence of cachexia) and twenty-four healthy control subjects. Fifty-nine patients were defined as cachectic, based on the percentage of weight loss compared with their previous normal weight. The remaining fifty-nine patients were defined as non-cachectic. Measurements were repeated in twenty-seven patients (sixteen with gastric cancer and eleven with colorectal cancer) 3 months after radical operation. Compared with the controls, the cachectic gastric cancer patients had high GH levels (1.36 v. 0.32 ng/ml; P=0.001), a trend towards high IGF-I levels (223.74 v. 195.15 ng/ml; P=0.128 compared with non-cachectic patients) and a low log IGF-I/GH ratio (2.55 and 2.66 v. 3.00; P=0.002), along with a decreased BMI; the cachectic colorectal cancer patients showed the biochemical characteristics of acquired GH resistance: high GH (0.71 v. 0.32 ng/ml; P=0.016), a trend towards decreased IGF-I levels (164.18 v. 183.24 ng/ml; P=0.127) and a low log IGF-I/GH ratio (2.54 v. 2.99; P=0.005), with increased IGF-I levels following radical surgery (200.49 v. 141.91 ng/ml; P=0.046). These findings suggest that normal GH reaction and sensitivity occur in gastric cancer patients, controlled by nutritional status, whereas acquired GH resistance develops in cachectic colorectal cancer patients, which may be caused by tumour itself.