OGFR mRNA在乳腺浸润性导管癌中的表达

目的探讨乳腺浸润性导管癌中OGFR mRNA的表达意义。方法采用逆转录-聚合酶链反应(RT-PCR)方法检测乳腺良性上皮增生、浸润性导管癌中OGFR mRNA的表达。结果 OGFR mRNA表达量在乳腺良性上皮增生组明显高于浸润性导管癌组(P<0.05);在浸润性导管癌中的表达与患者年龄、肿瘤体积、组织学分级、雌孕激素受体表达、c-erbB-2表达及淋巴结转移无关(P>0.05)。结论 OGFR mRNA表达减少可以作为乳腺浸润性导管癌的标志;OGFR在mRNA水平表达量减少,可能与乳腺癌的发生发展有关。

乳腺浸润性导管癌中OGF OGFR的表达研究

目的:探讨乳腺浸润性导管癌中OGF、OGFR的表达意义。方法:采用免疫组化SP法检测18例正常乳腺、12例乳腺腺病、8例乳腺异型上皮增生、21例浸润性导管癌组织中OGF、OGFR的表达。结果:在正常乳腺组、乳腺腺病组、乳腺异型上皮增生组、浸润性导管癌组中OGF表达率分别为55.43%、43.48%、34.50%、13.29%,各组间差异有统计学意义(P<0.01);OGFR表达率分别为68.80%、44.22%、40.00%、25.52%,各组间差异有统计学意义(P<0.01)。结论:乳腺组织中可能存在着OGF-OGFR的相互作用;OGF、OGFR的表达减少,减弱了OGF-OGFR的相互作用,可能促进了乳腺癌的发生、发展。增加OGF、OGFR的表达,促进两者的相互作用,可能对乳腺癌的治疗起着重要作用。

Overexpression of OGFr Downregulates Ovarian Cancer Cell Proliferation <i>In Vitro</i>and Inhibits Tumorigenesis

The opioid growth factor (OGF) and its receptor (OGFr) regulate human ovarian cancer cell proliferation through a tonically active inhibitory axis. We investigated the effect of OGFr overexpression on ovarian tumorigenesis. Clonal cell lines of SKOV-3 human ovarian cancer were established to stably overexpress OGFr. shRNA constructs were evaluated for antitumor activity in vitro, as well as in vivo using mouse models of s.c. and i.p. tumor transplantation. The 5 clonal cell lines were characterized by increases in OGFr protein (62% to 245%) and binding capacity (51% - 154%), and decreases (36% - 185%) in cell number, relative to untransfected wild-type (WT) cells and empty vector (EV) transfected clones. Nude mice receiving s.c. injection of 2 overexpressing OGFr cell lines (OGFr-3 and OGFr-22) had reduced tumor incidence, delayed tumor appearance (up to 12 days), and decreased tumor volume (up to 87%) relative to WT and EV controls. Mice injected i.p. with these clonal lines displayed reduced formation of tumor nodules (up to 95%), and depressed tumor weights (up to 99%) compared to WT and EV groups. DNA synthesis, but not cell survival, was depressed in cells and s.c. tumors overexpressing OGFr in comparison to the WT and EV groups. Angiogenesis was reduced up to 86% in clonal tumors compared to WT and EV groups. This preclinical evidence demonstrates that OGFr expression is a molecular determinant of ovarian cancer progression, and has important relevance to understanding the pathogenesis and treatment of this deadly disease.

The Opioid Growth Factor Inhibits Established Ovarian Cancer in Nude Mice and Can Be Combined with Taxol or Cisplatin to Enhance Growth Inhibition

Ovarian cancer is the 5th leading cause of cancer-related mortality in women. Seventy-five percent of ovarian cancer patients present in advanced stages, and receive cytoreductive surgery and adjuvant chemotherapy. However, within 2 years 65% of these patients relapse and thereafter only receive palliative care. Novel therapies based on the biology of these cancers are urgently needed. The opioid growth factor (OGF)-OGF receptor (OGFr) axis is an endogenous opioid system known to inhibit proliferation of human ovarian cancer cells in tissue culture, but does not affect cell survival. The present study determined whether OGF in combination with standard of care chemotherapy, provides an inhibitory effect on the growth of human ovarian cancer cells in vitro. In addition, this investigation assessed whether OGF biotherapy, alone or in combination with taxol or cisplatin, inhibits tumor growth in mice with xenografts of ovarian cancer. The combination of OGF (10–6 M) with taxol (10–9 M or 10–10 M) or cisplatin (0.01 ug/ml or 0.001 ug/ml) markedly reduced cell number and DNA synthesis in vitro to a greater extent than individual compounds. OGF, but not taxol or cisplatin, altered growth in an opioid receptor mediated and reversible manner. Female nu/nu mice inoculated subcutaneously with SKOV-3 cells, and treated with OGF (10 mg/kg) for 5 weeks commencing at the time tumors became measurable, had tumor volumes and weight that were reduced by up to 50% from animals receiving saline. The combination of OGF with taxol (3 mg/kg, weekly) or cisplatin (4 mg/kg, weekly for 2 weeks) for 37 days reduced tumor volumes and weight in contrast to mice receiving individual agents alone. Moreover, OGF treatment in mice receiving cisplatin provided protection against the weight loss associated with cisplatin alone. All treatments suppressed DNA synthesis and angiogenesis, whereas exposure to taxol or cisplatin, but not OGF, induced apoptosis. Additive inhibitory effects on DNA synthesis and angiogenesis were recorded in animals treated with both OGF and taxol, or OGF and cisplatin, in comparison to individual compounds alone. OGF and OGFr were detected in tumor tissue;however OGFr expression was reduced 51% - 81% by OGF treatment. This preclinical evidence demonstrates that OGF biotherapy markedly inhibits ovarian tumorigenesis in a non-toxic manner, and can be combined with taxol or cisplatin to provide an enhanced therapeutic benefit.

Opioid growth factor receptor promotes adipose tissue thermogenesis via enhancing lipid oxidation

The thermogenic brown and beige adipocytes consume fatty acids and generate heat to maintain core body temperature in the faceof cold challenges.Since their validated presence in humans,the activation of thermogenic fat has been an attractive target fortreating obesity and related metabolic diseases.Here,we reported that the opioid growth factor receptor(Ogfr)was highly expressedin adipocytes and promoted thermogenesis.The mice with genetic deletion of Ogfr in adipocytes displayed an impaired capacity tocounter environmental cold challenges.Meanwhile,Ogfr ablation in adipocytes led to reduced fatty acid oxidation,enhanced lipidaccumulation,impaired glucose tolerance,and exacerbated tissue inflammation under chronic high-fat diet(HFD)-fed conditions.At the cellular level,OGFr enhanced the production of mitochondrial trifunctional protein subunitα(MTPα)and also interacted withMTPα,thus promoting fatty acid oxidation.Together,our study demonstrated the important role of OGFr in fatty acid metabolismand adipose thermogenesis.