CN110042160A - A kind of method that alimentary system malignant tumour marker and its preparation inhibit alimentary system malignant tumour drug - Google Patents
A kind of method that alimentary system malignant tumour marker and its preparation inhibit alimentary system malignant tumour drug Download PDFInfo
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Abstract
The invention belongs to biomedicine fields, and in particular to a kind of method that alimentary system malignant tumour marker and its preparation inhibit alimentary system malignant tumour drug.Application of the HYAL2 as clinical diagnosis alimentary system malignant tumour passes through its expression in alimentary system malignant tumour of fluorescence quantitative PCR detection, according to expression, the molecular marker that HYAL2 is early diagnosed as alimentary system malignant tumour.The carrier of building interference HYAL2 gene expression is for inhibiting alimentary system malignant tumour drug；Utilize the carrier of building, drug of the preparation for applying or applying in vitro in vivo.Data prove the present invention through a large number of experiments, HYAL2 plays important regulating and controlling effect during the occurrence and development of alimentary system malignant tumour, interference HYAL2 gene expression significantly inhibits the proliferation and migration of alimentary system malignant tumour cell, and HYAL2 is expected to become the drug of new preparation prevention and treatment alimentary system malignant tumour.
Description
Technical field
The invention belongs to biomedicine field, particularly relates to a kind of alimentary system malignant tumour marker and its preparation inhibits
The method of alimentary system malignant tumour drug.
Background technique
With the change of socio-economic development and dietary structure, the disease incidence of alimentary system malignant tumour obviously rises, because
Death toll caused by alimentary system malignant tumour accounts for about all because of 3/4ths of number of cancer deaths, seriously threatens the mankind's
Life and health.Alimentary system malignant tumour mainly includes the cancer of the esophagus, gastric cancer, colorectal cancer, liver cancer, cholangiocarcinoma, cancer of pancreas.Digestion
Major Systems one of of the system as human body, malignant tumour have similar pathophysiological basis.Although at present
It is studied and has obtained a series of progress, but its definite molecular mechanism occurred cannot still define completely, and specific to certain one kind
The tumour of type is not also identical.It is at present to think that it is since the multiple factors such as environment, heredity, immune and endocrine are common more
The result of effect.Wherein the generation of gastric cancer is mostly related to the infection of helicobacter pylori, and clinically about 65% patients with gastric cancer is detectable
To helicobacter pylori infections；The generation of the cancer of the esophagus and the intake of nitrosamines substance, the shortage of certain microelements and vitamin
It is closely related；The generation of colorectal cancer mostly because of high fat diet and cellulose insufficiency of intake caused by；The gallbladder diseases such as gall stone
An important factor for chronic stimulation is gall-bladder carcinogenesis；Hepatitis B and hepatitis c virus infection, alcohol, cirrhosis, nitrosamines object
Matter and aflatoxins etc. are related to the generation of liver cancer；The pathogenic factor of cancer of pancreas is still not clear, but diabetes and chronic pancreatitis
The onset risk of patient is higher.
In the early stage that alimentary system malignant tumour occurs, pass through surgical discectomy or combined radiotherapy, chemotherapy technology energy
It is enough effectively to treat such disease.In addition, the modern therapies such as targeted therapy and immunization therapy are in treatment alimentary system malignant tumour side
It has made a breakthrough in face.But up to the present, the prognosis of middle and advanced stage alimentary system malignant tumour patient is still undesirable, such
Disease can not still be completely cured.The detection methods such as gastroscope, oesophagoscope, enteroscopy, B ultrasound and CT can effectively find that early stage disappears
Change System Malignant Tumor, therefore the death rate of such disease has been in be decreased obviously trend in recent decades.But digestive system is pernicious
The concealment of tumour onset, how unobvious early symptom is, and patient is diagnosed Shi Duoyi to middle and advanced stage, and treatment difficulty is big, Huan Zhesheng
It is poor to deposit rate.Therefore the effective molecular marker of screening and disclose its alimentary system malignant tumour generation in mechanism of action, it is right
It is of great significance in the early diagnosis of such disease and exploitation associated treatment drug.
Hyaluronic acid is a kind of macromolecular polysaccharide, is distributed in cytoplasm and cytoplasm as the proper constituent in human body
In, moist and lubricating action is played to cell and organ.Have in the fields such as beauty, anti-aging and Antiarthritic and widely answers
With.Hyaluronic acid is discharged to pericellular or thin after synthesizing through hyaluronic acid synthetase (Hyaluronan synthase, HAS)
Extracellular matrix, the proliferation and migration of rear adjustable cell in conjunction with its receptor.Hyaluronic acid is by hyaluronidase
It can be phagocytized by cells after (Hyaluronidase, HYAL) degradation or be transported through lymphatic system.Intracorporal HYAL mainly includes
A large amount of hyaluronic acid fragments often can be detected in HYAL1 and HYAL2 in many malignant tumours.Hyaluronic acid is also pernicious swollen
One of main matrix molecule of tumor, content increase the prognosis situation that will have a direct impact on malignant tumour.Detection can clinically be passed through
Hyaluronic acid or HYAL carry out the generation of diagnosing malignant tumor.Hyaluronic acid is not that independent play is made in the generation of malignant tumour
With.It is more studies have shown that HAS, HYAL and hyaluronic acid receptor have widely distributed, these families in malignant tumor tissue
Member cooperatively forms the metabolic chain of one with the interaction of cell peripheral interstitial, participates in the generation of malignant tumour, invasion, turns
The pathologic processes such as shifting, Tumor Angiongesis and lymphoid tissue infringement.
Research confirms that HYAL and the raising of hyaluronic acid level and the generation of Several Kinds of Malignancy are closely related.Such as: HYAL1
It is overexpressed in lung cancer, prostate cancer, oophoroma, it is also related to the invasion of breast cancer and transfer；HYAL2 in astrocytoma and
Three negative breast carcinomas increase, but abnormal expression reduces in non-Hodgkin lymphoma and melanoma.Its expression drop
Low or raising is closely related to clinical outcomes.But up to the present, expression of the HYAL2 in alimentary system malignant tumour and
The relationship occurred with alimentary system malignant tumour does not have been reported that also.
Therefore the present invention will test expression feelings of the HYAL2 gene in different types of alimentary system malignant tumour tissue
Condition, it is intended to provide new diagnosis marker for alimentary system malignant tumour detection and indicating risk, and study on this basis
The influence that alimentary system malignant tumour occurs is lowered in HYAL2 expression, it is intended to be provided newly for the treatment of alimentary system malignant tumour
Drug targeting, this is for improving the early diagnostic rate of alimentary system malignant tumour and improving alimentary system malignant tumour patient
Survival state has potential value.
Summary of the invention
For the early diagnostic rate for improving alimentary system malignant tumour, effectively inhibit its occurrence and development, the invention discloses
The application of molecular marker and its inhibition alimentary system malignant tumour that HYAL2 is early diagnosed as alimentary system malignant tumour.
The technical scheme of the present invention is realized as follows:
A kind of alimentary system malignant tumour marker, the marker are HYAL2.
The fluorescence quantification PCR primer pair of the alimentary system malignant tumour marker are as follows: forward primer such as SEQ ID NO:1
Shown, reverse primer is as shown in SEQ ID NO:2.
The preparation of alimentary system malignant tumour marker inhibits alimentary system malignant tumour pharmaceutical methods, and steps are as follows:
(1) using HYAL2 as desired control gene, the carrier of building interference HYAL2 gene expression；
(2) carrier in step (1), drug of the preparation for applying or applying in vitro in vivo are utilized.
The gene that HYAL2 expression is interfered in the step (1) includes knockout or silencing HYAL2 encoding gene, inhibits or drops
The transcription and translation function of low HYAL2, and one or more genes that interference HYAL2 protein function plays.
Carrier in the step (1) is viral vectors or non-viral gene silent carrier.
The viral vectors is adenovirus vector, gland relevant viral vector, retroviral vector or herpesvirus vector.
The non-viral gene silent carrier is CRISPR/Cas9 system gene knockout carrier, RNAi system gene silencing
Carrier or the carrier being transformed on this basis.
The alimentary system malignant tumour is the alimentary system malignant tumour tissue of the mankind, including the cancer of the esophagus, gastric cancer, knot are directly
Intestinal cancer, liver cancer, cholangiocarcinoma, cancer of pancreas.
The beneficial effects of the present invention are:
First: the present invention is disliked by reliable fluorescence quantifying PCR method, screening discovery HYAL2 in a plurality of types of digestive systems
Apparent increase, the high sensitivity of this method occur for the expression in property tumor tissues, and it is pernicious to can be used as digestive system for high specificity
The marker of clinical tumor early diagnosis.
Second: the present invention through a large number of experiments number it was demonstrated that HYAL2 alimentary system malignant tumour occurrence and development
Important facilitation is played in the process, and interference HYAL2 gene expression can significantly inhibit alimentary system malignant tumour cell
Proliferation and migration, HYAL2 are expected to become the drug target of new prevention and treatment alimentary system malignant tumour.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described, it should be apparent that, the accompanying drawings in the following description is only this
Some embodiments of invention for those of ordinary skill in the art without creative efforts, can be with
It obtains other drawings based on these drawings.
Fig. 1 is that quantitative fluorescent PCR analyzes HYAL2 in different type alimentary system malignant tumour tissue and Carcinoma side normal tissue
In mRNA expression；(figure A) wherein human esophageal carcinoma derives from the cancerous tissue (n=15) of patient with esophageal carcinoma, and cancer beside organism comes
Derived from the Carcinoma side normal tissue (n=15) of patient with esophageal carcinoma；(figure B) gastric adenocarcinoma tissue and Carcinoma side normal tissue (n=15)；(figure C)
Colon and rectum gland cancer tissue and Carcinoma side normal tissue (n=15)；(figure D) Tissues of Hepatocellular Carcinoma and Carcinoma side normal tissue (n=15)；(figure
E) cholangiocarcinoma and Carcinoma side normal tissue (n=15)；(figure F) Pancreatic Adenocarcinoma and Carcinoma side normal tissue (n=15)；β-actin
Internal reference crt gene as HYAL2.
Fig. 2 is quantitative fluorescent PCR analysis, A: the siRNA of transfection targeting HYAL2 in colorectal cancer HCT116 cell
(HYAL2-siRNA) after, the variation of intracellular HYAL2 gene mRNA levels；B: it is transfected in colorectal cancer HCT116 cell
After HYAL2-siRNA, the variation of intracellular HYAL2 protein expression level.
Fig. 3 is the influence for interfering HYAL2 gene pairs colorectal cancer HCT116 cell Proliferation, and colorectal cancer HCT116 cell turns
Dye is after HYAL2-siRNA 24,48,72 hours, the proliferative conditions of cancer cell.
Fig. 4 is the influence of scratch experiment Analysis interference HYAL2 gene pairs colorectal cancer HCT116 cell migration；A: Colon and rectum
Cancer HCT116 cell transfecting HYAL2-siRNA is after 24,48 hours, the healing state of cancer cell；B: colorectal cancer HCT116 cell
After transfection HYAL2-siRNA 24,48 hours, the healing rate schematic diagram of cancer cell.
Specific embodiment
Below in conjunction with the embodiment of the present invention, technical solution of the present invention is clearly and completely described, it is clear that institute
The embodiment of description is only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention,
Those of ordinary skill in the art's every other embodiment obtained under that premise of not paying creative labor, belongs to this hair
The range of bright protection.
Interference HYAL2 gene expression of the present invention includes the encoding gene for knocking out HYAL2, interference HYAL2 gene
Transcription or translation, and the entire bioprocess that interference HYAL2 protein function plays, although the specific mechanism of interference is not yet complete
It is clear, but do not interfere the realization of " interference ".
In some specific embodiments, one or more pharmaceutically acceptable adjuvants can be added in the drug,
Including but not limited to pharmaceutical adjuvants well known to granule, buffer, surfactant etc..
In some specific embodiments, the drug can be made including but not limited to microinjection agent, be suitable for turning
The dosage form of dye, these dosage forms can be prepared according to the method for pharmaceutical field routine.
The present invention is further described by the following examples, including using material and specific source.It is to be understood that
, these are exemplary, and are not intended to limit the present invention.With such as undertissue, cell, reagent, the type of instrument and model or
Property or the similar or identical material of function may be incorporated for implementation of the invention.Interference
Method in following examples is commonsense method unless otherwise specified.
Main material:
Note: unless otherwise stated, the reagent used in the present invention can be any suitable commercial reagent；Cell line can lead to
Cross commercially available acquisition.
One, the tissue expression analysis detection of HYAL2
1. the acquisition of cancer clinical sample
It is normal by the cancer of the esophagus, sdenocarcinoma of stomach, Colon and rectum gland cancer, hepatocellular carcinoma, cholangiocarcinoma, cancer of pancreas and the corresponding cancer of these cancerous tissues
Tissue is acquired from attached Huaihe River hospital, He'nan University.Entire acquisition and subsequent experimental process meet medical ethical moral requirement simultaneously
Follow strictly the principle of secrecy of case-data.After tissue sample underwent operative is taken out, it is cut into small pieces in cryopreservation tube is placed in liquid rapidly
It is saved backup in nitrogen.
2. RNA is extracted
1 mL Tri reagent is added in every 100 mg tissue, is placed on ice sufficiently homogenate disrupting tissue block, stands 5 points at room temperature
The BCP solution of 1/10 times of Tri reagen volume is added in Zhong Hou, is vortexed after mixing 15 seconds and is stored at room temperature 10 minutes.4 DEG C,
13,400g room temperature is centrifuged 15 minutes；Supernatant is transferred to 1.5 new mL centrifuge tubes, the isopropyl of equimultiple supernatant volume is added
Alcohol after being gently mixed by inversion for several times, is stored at room temperature 10 minutes, and 4 DEG C, 13400g is centrifuged after ten minutes, absorbs supernatant, is added 500
75% ethanol water of μ l, featheriness, which suspends, cleans RNA, and 4 DEG C, 13400g is centrifuged 5 minutes precipitating RNA.After absorbing supernatant, it is placed in
Room temperature ventilation is dried, 5 minutes or so dry.Addition is placed in 55 DEG C of water-baths 10 minutes without RNA enzyme water in right amount, to sufficiently molten
OD260 and OD280 absorption value is measured after solution.It is generally acknowledged that A260/A280 between 1.8 and 2.1 can be with preliminary judgement total serum IgE matter
Amount is preferable.
3. fluorescence quantitative PCR detection HYAL2 is horizontal
Take 2 μ g RNA by its reverse transcription at cDNA.Using cDNA as template, the 2 × SYBR of primer and PCR for being directed to HYAL2 is used
Green qPCR Mixture is expanded on 7500 fluorescence quantitative PCR instrument of ABI.PCR condition are as follows: 50 DEG C 20 seconds；95
DEG C 10 minutes；95 DEG C 10 seconds；60 DEG C 1 minute, repeat 40 circulation；The CT value of sample HYAL2 amplification is measured, with internal reference
The CT value of gene β-actin is standardized correction.Gained CT value uses 2-Δ∆CTMethod is calculated, between more different samples
The difference of HYAL2 content.HYAL2 forward primer used is as described in SEQ ID NO:1；HYAL2 reverse primer such as SEQ ID NO:2
It is described.Internal reference compares β-actin forward primer as described in SEQ ID NO:3；Internal reference compares β-actin reverse primer such as SEQ ID
Described in NO:4.
As a result: as shown in Figure 1, the mRNA level in-site of HYAL2 gene is in human esophageal carcinoma (figure compared with Carcinoma side normal tissue
A), gastric adenocarcinoma tissue (figure B), Colon and rectum gland cancer tissue (figure C), Tissues of Hepatocellular Carcinoma (figure D), cholangiocarcinoma (figure E), pancreas
It is obvious in cancerous tissue (figure F) to rise,P< 0.001.Show that the abnormal raising of the expression of HYAL2 is pernicious with digestive system
The generation of tumour is closely related.
Two, interference HYAL2 gene expression can obviously inhibit proliferation, invasion and the clonality of colon cancer cell
1. cell culture
Human colon cancer cell line HCT116 cell is cultivated in DMEM culture medium (Thermo, USA).Contain in culture medium
10% fetal calf serum (Gibco, USA), penicillin (100 U/mL) and streptomysin.All cells are placed in 37 DEG C of incubators, 5%
CO2Under the conditions of cultivate.
2. cell transfecting
To starting to transfect after 60% or so density after HCT116 plating cells about 20 hours, transfection setting HYAL2-siRNA is interfered
The general negative control group of group, NC-siRNA.Transfection reagent used is liposome 2000, and transfection method is carried out referring to specification.
3. the detection of intracellular HYAL2 gene mRNA levels
Continue culture 36 hours after transfection, collects cell.According to the method in embodiment 1, the total serum IgE of cell, reverse transcription are extracted
The method for utilizing quantitative fluorescent PCR afterwards, the variation of the intracellular HYAL2 gene mRNA levels of HCT116 after detection transfection.
4. the detection of intracellular HYAL2 expression of gene protein level
Continue culture 48 hours after transfection, cell is collected by centrifugation after digestion.Add 100 μ L cell pyrolysis liquid lytic cells,
13200rpm, 4 DEG C are centrifuged 15 minutes, extract total protein of cell；After detecting protein concentration, every group of sample take 20 μ g samples and 4 ×
SDS-PAGE loading buffer mixing, 95 DEG C of heat treatment 5min.With 10% SDS-PAGE glue protein isolate；Electrophoresis knot
Shu Hou, transferring film 60 minutes in Transfer Buffer；It is closed blotting membrane 1 hour using 5% skim milk, TBST is washed 3 times
Afterwards plus diluted primary antibody, 4 DEG C are incubated overnight；After TBST is washed 3 times, secondary antibody diluent appropriate is added, is incubated at room temperature 1 hour.
TBST is washed 3 times again；After developed fixing processing, gel imaging system is taken pictures, and carries out ash to band using Image J software
Spend analysis processing.
As a result: as shown in Fig. 2, quantitative fluorescent PCR is analysis shows that (figure A), transfection HYAL2-siRNA can be significantly inhibited
The mRNA level in-site of the intracellular HYAL2 of HCT116, and can inhibit its protein expression level (figure B),P< 0.01.It should be the result shows that logical
It is practicable for crossing the level of abnormal raised HYAL2 in exogenous method interference colon cancer cell.
Three, interference HYAL2 gene can inhibit the proliferation of colon cancer cell
Using the proliferative conditions of CCK-8 cell proliferation detecting kit detection cell.By 5 × 105A HCT116 cell is laid on 6
In the culture dish of hole, according to the method in embodiment 2, the general negative control of HYAL2-siRNA and NC-siRNA is transfected.After transfection
6 hours vitellophags, by two transfection group cell inoculations into 96 orifice plates, 1 × 1046 weights are arranged in/hole, each transfection group
Multiple holes, and 4 detection time points are set.The CCK-8 solution of 10 μ L is added in the adherent backward every hole of cell, and culture plate is placed in culture
After case is incubated for 4 hours, the absorbance at 450nm is measured with microplate reader.Then difference 24 hours, 48 hours and 72 after transfection
Hour is detected.Cell Proliferation curve is drawn according to the O.D value of measurement.
As a result: as shown in figure 3, compared with the control group, transfecting after HYAL2-siRNA 24 hours, the proliferation of HCT116 cell
Speed begins to slow down, at this time the speed of growth of two groups of cells have statistical difference (P< 0.05).48 is small after transfection
When, the speed of growth of HYAL2-siRNA group cell be significantly lower than control group (P< 0.01).And with the extension of time, to knot
The depression effect of colon-cancer cell proliferation it is further obvious (P< 0.001).Show to interfere endogenous HYAL2 gene that can effectively inhibit
The proliferation of colon cancer cell.Thus it is concluded that interfering the expression of HYAL2 gene in alimentary system malignant tumour tissue or can have
Effect inhibits the proliferation of cancer cell.
Four, interference HYAL2 gene can inhibit the transfer ability of colon cancer cell
1. HCT116 cell is laid in 6 hole culture dishes, cell, which grows to 60% or so density, before transfecting is advisable, according to embodiment
Method in three transfects the general negative control of HYAL2-siRNA or NC-siRNA respectively.It is sterile with 200 μ L after transfection 6 hours
Liquid-transfering gun pipette tips are in " one " stroke trace on cell monolayer, and PBS cleaning removes the cell under drawing three times, the training for being free of serum is added
Feeding base continues to cultivate cell.The position mark that scratch is smooth at one is first selected under 4 power microscopes, and takes pictures and is denoted as 0h control, so
Culture dish is placed in incubator afterwards to continue to cultivate, and in 24 hours and 48 hours acquisition same position cell images.Use Image
The area and width of 6.0 software of Pro Plus measurement scratch.
The healing rate of cell: (width 1- width 2)/width 1, width 1 and width 2 are respectively scratch at 0 hour and 24/
48 hours width, scratch width are the ratio of scratch area and length.
As a result: as shown in figure 4, compared with the control group, after transfection HYAL2-siRNA 24 hours, the scratch of colon cancer cell
Healing rate occur being substantially reduced (P< 0.05)；48 hours after transfection, the scratch wound of cellular control unit heals completely, and
The scratch healing rate of HYAL2-siRNA transfection group cell only 50% or so (P< 0.05), show that transfecting HYAL2-siRNA can show
Write the transfer ability for inhibiting colon cancer cell.Therefore interference alimentary system malignant tumour tissue in HYAL2 gene expression or can
Effectively inhibit the diffusion and transfer of cancer cell.
Statistical analysis: all data take the average value of independent repetition experiment three times, and standard deviation (SD) utilizes GraphPad
Method in Prism 8.0 carries out data analysis.P < 0.05 thinks with statistical significance.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Within mind and principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
<110>He'nan University
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Claims (8)
1. a kind of alimentary system malignant tumour marker, it is characterised in that: the marker is HYAL2.
2. alimentary system malignant tumour marker described in claim 1, it is characterised in that: the alimentary system malignant tumour mark
The fluorescence quantification PCR primer pair of will object are as follows: forward primer is as shown in SEQ ID NO:1, reverse primer such as SEQ ID NO:2 institute
Show.
3. alimentary system malignant tumour marker preparation described in claim 1 inhibits alimentary system malignant tumour pharmaceutical methods,
It is characterized in that, steps are as follows:
(1) using HYAL2 as desired control gene, the carrier of building interference HYAL2 gene expression；
(2) carrier in step (1), drug of the preparation for applying or applying in vitro in vivo are utilized.
4. alimentary system malignant tumour marker preparation according to claim 3 inhibits alimentary system malignant tumour drug side
Method, it is characterised in that: the gene of interference HYAL2 expression includes knockout or silencing HYAL2 encoding gene, suppression in the step (1)
System or the transcription and translation function of reducing HYAL2, and one or more genes that interference HYAL2 protein function plays.
5. alimentary system malignant tumour marker preparation according to claim 3 inhibits alimentary system malignant tumour drug side
Method, it is characterised in that: the carrier in the step (1) is viral vectors or non-viral gene silent carrier.
6. alimentary system malignant tumour marker preparation according to claim 5 inhibits alimentary system malignant tumour drug side
Method, it is characterised in that: the viral vectors is adenovirus vector, gland relevant viral vector, retroviral vector or blister sore
Poisonous carrier.
7. alimentary system malignant tumour marker preparation according to claim 5 inhibits alimentary system malignant tumour drug side
Method, it is characterised in that: the non-viral gene silent carrier is CRISPR/Cas9 system gene knockout carrier, RNAi system base
The carrier being transformed because of silent carrier or on this basis.
8. inhibiting digestive system pernicious swollen according to the described in any item alimentary system malignant tumour marker preparations of claim 3-7
Tumor medicine method, it is characterised in that: the alimentary system malignant tumour is the alimentary system malignant tumour tissue of the mankind, including food
Pipe cancer, gastric cancer, colorectal cancer, liver cancer, cholangiocarcinoma, cancer of pancreas.
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| CN107012207A (en) * | 2017-03-03 | 2017-08-04 | 北京化工大学 | LRP5 is used as clinical diagnosis and the application of suppression digestive system tumor |
| CN109022584A (en) * | 2018-08-30 | 2018-12-18 | 江南大学附属医院 | A kind of molecular marker of the cancer of the esophagus and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107012207A (en) * | 2017-03-03 | 2017-08-04 | 北京化工大学 | LRP5 is used as clinical diagnosis and the application of suppression digestive system tumor |
| CN109022584A (en) * | 2018-08-30 | 2018-12-18 | 江南大学附属医院 | A kind of molecular marker of the cancer of the esophagus and application thereof |
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| MELANIE AIERTHALER等: "S100P and HYAL2 as prognostic markers for patients with triple-negative breast cancer", 《EXPERIMENTAL AND MOLECULAR PATHOLOGY》 * |
| ZHIMING JIN等: "The suppressive role of HYAL1 and HYAL2 in the metastasis of colorectal cancer", 《JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY》 * |
| 周敏等: "HYAL2基因沉默对卵巢癌 SKOV3细胞增殖和侵袭的影响", 《第四军医大学学报》 * |
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