CN109856400B - Use of ceramide C24 as biomarker for diagnosing gallbladder cancer - Google Patents
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Abstract
The invention provides application of ceramide C24 as a biomarker for diagnosing gallbladder cancer. Ceramide C24 was found by experiment to be significantly upregulated in gallbladder cancer tissues and serum. Serotype C24 is of great diagnostic value, especially as a complementary means for diagnosing CA19-9 negative patients.
Description
Technical Field
The invention belongs to the field of biomedicine, and relates to a detection marker, in particular to application of ceramide C24 as a biomarker in diagnosing gallbladder cancer.
Background
Gallbladder cancer is the most common malignant tumor (41.3 percent) of the biliary tract system, and the 6 th site of the incidence rate of the tumor in the endemic digestive tract. The early diagnosis of the gallbladder cancer is difficult, the malignancy is high, the disease progresses rapidly, the surgical radical resection rate is low, the prognosis is very poor, and the total survival rate in 5 years is only 5 percent3. Gallbladder cancer cells have poor reactivity to common first-line chemotherapy drugs such as 5-fluorouracil, cisplatin, gemcitabine, etc., and the remission rate of chemotherapy is only 5% -10%. Considering the factors of low surgical radical resection rate, high surgical difficulty, many complications and the like, the long-term survival rate is difficult to improve only by surgical operation. Early symptoms of gallbladder cancer are not obvious and specificity of clinical symptoms is not strong, so that early diagnosis is very difficult, and the treatment effect and prognosis of patients are seriously influenced. Most patients are already in the advanced stage at the time of clinical diagnosis, and the precious opportunity of radical surgery is lost. Therefore, screening effective early diagnosis markers and improving the early screening rate of the gallbladder cancer are the key points for further prolonging the life cycle of gallbladder cancer patients and improving the long-term survival rate. The preferred marker in clinical practice is CA19-9, CEA and the like. However, neither CA19-9 nor CEA gave satisfactory results in clinical screening and early diagnosis. In gallbladder cancer patients, the CA19-9 level of many patients is not abnormal, so that the development of a diagnosis method for CA19-9 negative patients has very important value and clinical practice significance.
Ceramide C24(Ceramide-24) Molecular weight of 636.087 and molecular formula of C41H81NO3The structural formula is shown as follows.
Disclosure of Invention
The invention aims to provide application of ceramide C24 as a biomarker in diagnosing gallbladder cancer, and aims to solve the technical problem that clinical markers CA19-9, CEA and the like in the prior art have poor effects on early diagnosis of gallbladder cancer.
The invention provides application of ceramide C24 as a biomarker for diagnosing gallbladder cancer.
Ceramide C24 was found by experiment to be significantly upregulated in gallbladder cancer tissues and serum. Serotype C24 is of great diagnostic value, especially as a complementary means for diagnosing CA19-9 negative patients.
Compared with the prior art, the invention has the advantages of positive and obvious technical effect. The invention adopts ceramide C24 as a diagnostic marker to detect the gallbladder cancer, has high sensitivity and accuracy, and particularly has strong application value and prospect for CA19-9 and CEA negative patients.
Drawings
Fig. 1 is a circuit diagram of a research queue technology.
FIG. 2 shows the abundance test of Ceramide of different lengths in gallbladder cancer tissue and paracarcinoma tissue, among which Ceramide C16(Ceramide-16) Ceramide C20(Ceramide-20) Ceramide C24(Ceramide-24) The abundance of the compound is obviously increased in gallbladder cancer tissues, while Ceramide C18(Ceramide-18) Abundance ofAnd (4) descending.
FIG. 3 shows the measurement of the serum abundance of ceramides of different lengths in healthy people, gallstones and patients with gallbladder cancer, wherein Ceramide C16(Ceramide-16) Ceramide C20(Ceramide-20) Ceramide C24(Ceramide-24) The abundance of the compound is obviously increased in the patients with gallbladder cancer, while Ceramide C18(Ceramide-18) The abundance of (a) decreases.
FIG. 4A shows PLS-DA analysis suggesting that Ceramide-24 is able to discriminate well between healthy populations and gall bladder stones and cancer in study cohort 1.
FIG. 4B shows PLS-DA analysis suggesting that Ceramide-24 is able to discriminate well between healthy populations and gall bladder stones and cancer in study cohort 2.
FIG. 5 shows the second queue of samples for Ceramide-24Is significantly elevated in gallbladder cancer, while healthy people are indistinguishable from gallstone.
FIG. 6A shows that the AUC value in the first cohort is 0.889 (healthy population versus gallbladder cancer) by ROC curve analysis. Accuracy and sensitivity were 78.08% and 91.49%, respectively.
Fig. 6B shows AUC values in the second cohort 0.9513 (healthy population versus gallbladder cancer) by ROC curve analysis. Accuracy and sensitivity were 88.24% and 100%.
FIG. 7A shows that C24 is able to discriminate well between gallbladder cancer and gallbladder stone, with AUC values of sum 0.91470.95 (gallbladder stone vs. gallbladder cancer) in both cohorts. The accuracy and sensitivity were 78.08%/91.49% and 88.24%/100% in the two queues, respectively.
Fig. 7B shows AUC values in the second cohort 0.9513 (healthy population versus gallbladder cancer) by ROC curve analysis.
FIG. 8 shows Ceramide-24Has good diagnostic value for CA19-9 negative gallbladder cancer patients. Sensitivity and accuracy were 85.71% and 93.88%.
Detailed Description
Example 1 ceramide serum level assay
The study was divided into two cohorts, the first one being the training cohort and 139 samples were collected. The collection of the healthy controls was 47 cases, 49 cases of gallbladder stones and 43 cases of gallbladder cancer. The healthy control is volunteers examined by a medical examination center in the ren Ji hospital, and the examination result shows that no common diseases are found. The cholelithiasis is confirmed by gallbladder-pancreas surgery in ren Ji hospital, collecting preoperative blood, and confirming the cholelithiasis again after operation. The gallbladder cancer is a patient with confirmed gallbladder cancer in gallbladder-pancreas surgery of ren Ji hospital, blood before operation is collected, and the gallbladder cancer is confirmed again in postoperative pathology. All enrollees were older than 18 years of age.
The second queue was the validation queue, and 92 specimens were collected. The selection criteria are the same as the above on 28 cases of physical examination healthy controls, 30 cases of gallbladder stones and 34 cases of gallbladder cancer. The grouping procedure is shown in FIG. 1.
100ul of serum was collected, 400ul of acetonitrile was added, mixed well, centrifuged at 14000RPM for 5min, and the protein sample was removed. The supernatant was transferred to a new EP tube. 100ul of supernatant was taken and 375ul of methanol was added: chloroform (2:1) extract and equal amount of C17-ceramide (1ug) were used as standard. The extract is determined by high performance liquid chromatography/tandem mass spectrometry (((III)
4000and 6500, SCIEX, Framingham, MA, USA). The MS/MS transitions (M/z) are 510 → 264for C14, 538.4 → 264.2for C16, 552.5 → 264.2for C17, 564 → 264.2for C18:1, 566.5 → 264.2for C18, 594.6 → 264.2for C20, 648 → 264.2for C24:1, 650.7 → 264.2for C24.C 17552.5 → 264.2. ceramides of different lengths are all standardized for quantitative analysis using C17 (ref. Suzuki M, Cao K, Kato S, Komizu Y, Mitani N, Tanaka K et al (2016.). Targeting ceramide synthase 6-dependent-reagent-protein in additive 254. calcium chloride 126. 265. conversion of calcium chloride 265).
The main detection indexes are as follows:
C14-ceramide，C16-ceramide，C18-ceramide，C18:1-Ceramide C20-ceremide，C24-ceramide，C24:1-ceramide。
detection of ceramide in gallbladder cancer tissue:
taking pathological gallbladder for accurate diagnosisApproximately 10mg of cancer and corresponding paraneoplastic tissue, 1ug of C17-ceramide standard and 375ul of methanol: chloroform (2: 1). Crushing the tissue by a tissue crusher to extract ceramide. The extract is determined by high performance liquid chromatography/tandem mass spectrometry (((III)
4000and 6500, SCIEX, Framingham, MA, USA). The MS/MS transitions (m/z) are 510 → 264for C14, 538.4 → 264.2for C16, 552.5 → 264.2for C17, 564 → 264.2for C18:1, 566.5 → 264.2for C18, 594.6 → 264.2for C20, 648 → 264.2for C24:1, 650.7 → 264.2for C24, and ceramides of different lengths are quantitatively analyzed by C17 in a standardized manner. (references Suzuki M, Cao K, Kato S, Komizu Y, Mizutani N, Tanaka K et al (2016.) Targeting ceramide synthases 6-dependent metastasis-protein biosynthesis in luminescence cancer cells. the Journal of clinical information 126: 254-.
The main detection indexes are as follows:
C14-ceramide，C16-ceramide，C18-ceramide，C18:1-Ceramide C20-ceremide，C24-ceramide，C24:1-ceramide。
the results show that:
c16, C20 and C24 were significantly elevated in gallbladder cancer tissue (fig. 2). C18 was significantly down-regulated in gallbladder cancer.
2. In the first cohort samples, sera C16, C20, and C24 were significantly up-regulated in gallbladder cancer sera. In contrast, C18 was down-regulated in gallbladder cancer serum. (FIG. 3).
3. PLS-DA analysis shows that the separation effect is good for two cohort samples, namely healthy people, and gall bladder stones and gall bladder cancers can be well separated. And C24 is the main factor responsible for this separation, see fig. 4A and 4B. The second cohort of samples also suggested a significant increase in C24 in gallbladder cancer, and no distinction between healthy persons and gallstone (see fig. 5).
ROC curve analysis suggests: AUC was 0.889 and 0.9513 in the first and second cohorts, respectively (vs gallbladder cancer in healthy population). Accuracy and sensitivity were 78.08% and 91.49% vs 88.24% and 100% in the two queues, respectively. See fig. 6A and 6B.
5. At the same time, C24 was able to discriminate well between gallbladder cancer and gallbladder stones, with AUC values of 0.9147 and 0.95 in both cohorts, see FIGS. 7A and 7B.
6. More importantly, C24 still has good diagnostic value for CA19-9 negative gallbladder cancer patients. Sensitivity and accuracy were 85.71% and 93.88%. See fig. 8.
To summarize: through the experiments, the ceramide C24 is found to be remarkably up-regulated in gallbladder cancer tissues and serum. Serotype C24 has great diagnostic value, especially as a complementary means to diagnose CA19-9 negative patients.
Claims (1)
1. Use of a reagent for detecting ceramide C24 in The preparation of a reagent for diagnosing gallbladder cancer, as determined by HPLC/tandem mass spectrometry, The MS/MStransitions being 510 → 264m/z for C14, 538.4 → 264.2 m/z for C16, 552.5 → 264.2 m/z for C17, 564 → 264.2 m/z for C18:1, 566.5 → 264.2 m/z for C18, 594.6 → 264.2 m/z for C20, 648 → 264.2 m/z for C24:1, 650.7 → 264.2 m/z for C24, and ceramides of different lengths being quantitatively analyzed by C17.
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| AU2014201215A1 (en) * | 2008-06-16 | 2014-04-03 | Academia Sinica | Globo h and related anti-cancer vaccines with novel glycolipid adjuvants |
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| CN1300842A (en) * | 1999-12-21 | 2001-06-27 | 复旦大学 | Polypeptide-hydrogen peroxidase 10 and polynucleotide for coding this polypeptide |
| CN104422764A (en) * | 2013-09-04 | 2015-03-18 | 深圳市艾瑞生物科技有限公司 | Glycoprotein-type tumor marker immunochromatographic test strip as well as preparation method and application thereof |
| EP3919507A3 (en) * | 2015-07-01 | 2022-01-12 | Immatics Biotechnologies GmbH | Novel peptides and combination of peptides for use in immunotherapy against ovarian cancer and other cancers |
| CN105044361B (en) * | 2015-08-14 | 2017-07-28 | 山东省肿瘤防治研究院 | A kind of diagnostic marker and its screening technique for being suitable for esophageal squamous cell carcinoma early diagnosis |
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| CN1315532A (en) * | 2000-03-29 | 2001-10-03 | 上海博德基因开发有限公司 | Polypeptide-human peroxidase 11 and polynucleotide for coding it |
| AU2014201215A1 (en) * | 2008-06-16 | 2014-04-03 | Academia Sinica | Globo h and related anti-cancer vaccines with novel glycolipid adjuvants |
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