Oncofetal HLF transactivates c-Jun to promote hepatocellular carcinoma development and sorafenib resistance.

BACKGROUND AND AIMS: The unique expression pattern makes oncofetal proteins ideal diagnostic biomarkers and therapeutic targets in cancer. However, few oncofetal proteins have been identified and entered clinical practice. METHODS: Fetal liver, adult liver and hepatocellular carcinoma (HCC) tissues were employed to assess the expression of hepatic leukaemia factor (HLF). The impact of HLF on HCC onset and progression was investigated both in vivo and in vitro. The association between HLF and patient prognosis was determined in patient cohorts. The correlation between HLF expression and sorafenib benefits in HCC was further evaluated in patient cohorts and patient-derived xenografts (PDXs). RESULTS: HLF is a novel oncofetal protein which is reactivated in HCC by SOX2 and OCT4. Functional studies revealed that HLF transactivates c-Jun to promote tumour initiating cell (TIC) generation and enhances TIC-like properties of hepatoma cells, thus driving HCC initiation and progression. Consistently, our clinical investigations elucidated the association between HLF and patient prognosis and unravelled the close correlation between HLF levels and c-Jun expression in patient HCCs. Importantly, HLF/c-Jun axis determines the responses of hepatoma cells to sorafenib treatment, and interference of HLF abrogated c-Jun activation and enhanced sorafenib response. Analysis of patient cohorts and PDXs further suggests that HLF/c-Jun axis might serve as a biomarker for sorafenib benefits in HCC patients. CONCLUSIONS: Our findings uncovered HLF as a novel oncofetal protein and revealed the crucial role of the HLF/c-Jun axis in HCC development and sorafenib response, rendering HLF as an optimal target for the prevention and intervention of HCC.

Single-cell transcriptomic analyses reveal distinct dorsal/ventral pancreatic programs.

The pancreas of vertebrates is separately derived from both the dorsal and ventral endodermal domains. However, the difference between these two programs has been unclear. Here, using a pancreatic determination gene, Pdx1, driven GFP transgenic mouse strain, we identified Pdx1-GFP highly expressing cells (Pdx1high) and Pdx1-GFP lowly expressing cells (Pdx1low) in both embryonic dorsal Pdx1-expressing region (DPR) and ventral Pdx1-expressing region (VPR). We analyzed the transcriptomes of single Pdx1low and Pdx1high cells from the DPR and VPR. In the VPR, Pdx1low cells have an intermediate progenitor identity and can generate hepatoblasts, extrahepatobiliary cells, and Pdx1high pancreatic progenitor cells. In the DPR, Pdx1high cells are directly specified as pancreatic progenitors, whereas Pdx1low cells are precocious endocrine cells. Therefore, our study defines distinct road maps for dorsal and ventral pancreatic progenitor specification. The findings provide guidance for optimization of current ß-cell induction protocols by following the in vivo dorsal pancreatic specification program.

Embryonic soluble human leukocyte antigen-G as a marker of embryo competency in assisted reproductive technology for Chinese women.

OBJECTIVE: To investigate whether embryonic soluble human leukocyte antigen-G (sHLA-G) could be a noninvasive marker for embryo competency in assisted reproductive technology (ART), which is still controversial due to the different detection assays used and the different culture conditions in laboratories. STUDY DESIGN: Based on the standardization of IVF procedures and the embryo culture condition, a total of 205 embryo culture supernatants (ESs) from 92 ART cycles were evaluated for sHLA-G contents by chemiluminescent ELISA assay. RESULTS: sHLA-G presence could be detected in 30.7% of the ESs tested. In the cycles where at least one of the embryos transferred was positive for sHLA-G, 51.9% of patients (27/52) achieved a clinical pregnancy. In cycles where none of the embryos transferred secreted detectable amounts of sHLA-G, the pregnancy rate was only 30.0% (12/40, p < 0.05). The implantation rate in sHLA-G-positive cycles was also significantly higher (31.5%) than that in sHLA-G-negative cycles (14.9%, p < 0.05). CONCLUSION: The results suggested sHLA-G in ESs as a potential marker of embryo competency in ART programs for the Chinese population.

Comparative evaluation of surgical stress of laparoscopically assisted vaginal radical hysterectomy and lymphadenectomy and laparotomy for early-stage cervical cancer.

The aim of this study was to objectively evaluate the benefits of laparoscopically assisted vaginal radical hysterectomy and lymphadenectomy for early-stage cervical cancer. Clinical data were prospectively collected from patients with IA-IIB cervical cancer who underwent laparoscopically assisted vaginal radical hysterectomy (n1=33) and laparotomy (n2=30). Peripheral blood samples were obtained prior to surgery and at 1 and 2 h into the operation, as well as on days 1, 4 and 7 following surgery to measure serum interleukin-6, C-reaction protein and cortisol. Results showed that there was no conversion to laparotomy in the laparoscopy group. The average blood loss was 317.23±217.20 ml (laparoscopy group) and 872.58±693.16 ml (laparotomy group). No significant difference was found in the number of resected pelvic lymph nodes (19.74±7.43 in the laparoscopy group and 20.35±6.62 in the laparotomy group). At days 1 and 7 after surgery, the serum IL-6 level was significantly different in the laparoscopy and laparotomy groups (day 1: laparoscopy group 17.14±16.53 pg/ml and laparotomy group 34.32±20.97 pg/ml, p=0.001; day 7: laparoscopy group 6.7±7.21 pg/ml and laparotomy group 17.54±16.47 pg/ml, p=0.001). The serum CRP level was significantly different at days 1 and 7 after the operation (day 1: laparoscopy group 7024.72±949.12 ng/ml and laparotomy group 7586.61±869.42 ng/ml, p=0.018; day 7: laparoscopy group 4357.71±2108.85 ng/ml and laparotomy group 6967.96±995.02 ng/ml, p<0.001). A significant difference was noted in the serum cortisol level at day 4 after the operation (122.29±65.17 ng/ml in the laparoscopy group and 186.76±68.61 ng/ml in the laparotomy group, p<0.001). In conclusion, the differences in clinical data and the various parameters pertinent to surgical stress evaluated in this study suggest that laparoscopic surgery for cervical cancer causes less postoperative stress than conventional open surgery.

[Preliminary study on laparoscopically robotic assisted radical hysterectomy and pelvic lymphadenectomy on cervical cancer.].

OBJECTIVE: To evaluate the feasibility of laparoscopically robotic assisted radical hysterectomy and pelvic lymphadenectomy in treatment of cervical cancer. METHODS: From Dec. 2008 to Aug. 2009, 5 cervical cancer patients at stage Ib1 to IIa underwent laparoscopically robotic assisted radical hysterectomy and pelvic lymphadenectomy. The following clinical parameters were recorded and compared, including operative time, blood loss, intraoperative and postoperative complications, the changes of hemoglobin before and after surgery, postoperative temperature, the time of postoperative anus exhaust and urination, hospitalization, pathologic exam, and the number of lymph nodes. RESULTS: Laparoscopically robotic assisted radical hysterectomy and pelvic lymphadenectomy were performed successfully on those 5 patients without the conversion to laparotomy. No intraoperative and postoperative complications were observed. The operative time were 305, 365, 275, 240 and 245 minutes, respectively, with a mean value of 286 minutes. Estimated blood loss was 200, 400, 650, 300 and 400 ml, respectively. The mean blood loss was 390 ml. Temperatures of all patients were not higher than 37.5 degrees C and anus exhaust was recovered at 36 hours after surgery. Those five patients were hospitalized for 11, 13, 9, 12 and 12 days respectively. Squamous carcinoma of cervix were diagnosed by the pathologic examination. The resected margin of vagina and parametrium was clear. The numbers of pelvic lymph nodes were 14, 22, 16, 21 and 18, respectively. No evidence of lymph nodes metastasis was found. CONCLUSION: Laparoscopically robotic assisted radical hysterectomy and pelvic lymphadenectomy is feasible as a novel approach in the treatment of cervical cancer.