CN116004835A - Application of FMN1 gene in preparing medicine for resisting digestive tract tumor - Google Patents
Application of FMN1 gene in preparing medicine for resisting digestive tract tumor Download PDFInfo
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Abstract
The invention belongs to the technical field of biological medicines, and particularly relates to application of an FMN1 gene in preparation of a KRAS mutation resistant digestive tract tumor drug. Aiming at the technical problem that the KRAS mutant tumor is difficult to achieve effective treatment by a treatment means due to the diversity of biological properties, and the targeted drug specially aiming at KRAS mutation is not marketed at present, the invention utilizes a tissue chip to find that FMN1 is highly expressed in the KRAS mutant digestive tract tumor, and utilizes a database to find that FMN1 is related to prognosis of the KRAS mutant digestive tract tumor. The invention discovers that the knock-down FMN1 can inhibit migration and invasion of KRAS mutant digestive tract tumor cells, and achieves the effect of resisting tumor metastasis. Therefore, FMN1 can be used as a potential target point of KRAS mutant digestive tract tumor and as a development direction of KRAS mutant digestive tract tumor therapeutic drugs.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of an FMN1 gene in preparation of a KRAS mutation resistant digestive tract tumor drug.
Background
The digestive tract tumor comprises colorectal cancer, pancreatic cancer and intrahepatic bile duct cancer, and has high-frequency KRAS mutation. The survival of KRAS mutated patients is far lower than those without KRAS mutations. However, KRAS mutant proteins are complex in structure and difficult to target, and KRAS mutant tumors are difficult to achieve effective treatment by a therapeutic means due to the diversity of biological properties. Currently, no targeted drug specifically directed to KRAS mutation is marketed, and thus, development of a new antitumor target directed to KRAS mutation is urgent.
FMN1 is located on chromosome 15 and encodes 1420 amino acids and the formin-1 protein. Recent studies indicate that FMN1 can promote glioma migration, while knockout of FMN1 can inhibit glioma cell migration. Multiple susceptible SNP loci related to FMN1 gene are reported to be closely related to tumorigenesis of pancreatic cancer, colorectal cancer, prostate cancer and the like.
Disclosure of Invention
Aiming at the defects of the prior art, the research of the invention discovers that FMN1 is highly expressed in digestive tract tumors and is related to poor prognosis, however, the action mechanism of FMN1 in the occurrence and development of digestive tract tumors is not clear, and the present has a few literature reports. In view of the above problems, the present invention aims to determine the relationship between FMN1 and KRAS mutant gut tumor, provide a new target for the preparation of medicine for KRAS mutant gut tumor, and provide a new application of FMN 1.
The invention provides application of FMN1 gene or its expression product as target spot in preparing medicine for preventing or treating digestive tract tumor.
The invention also provides application of the agent for targeting the FMN1 gene or the expression product thereof in preparing medicines for preventing or treating digestive tract tumors.
Wherein the agent targeting the FMN1 gene or its expression product is selected from the group consisting of: at least one of a nucleic acid, a polypeptide, a ribonucleoprotein complex, or a small molecule drug.
Preferably, the agent targeting the FMN1 gene or its expression product is selected from: at least one of antisense oligonucleotide, siRNA, dsRNA ribozyme, esiRNA, shRNA and small molecule drug.
The invention also provides application of the FMN1 gene or an expression product thereof serving as a target spot in preparing a drug screening device, wherein screening refers to screening drugs for preventing or treating digestive tract tumors.
Preferably, the drug screening device comprises a detection reagent for determining the level or activity of the FMN1 gene or its expression product.
Preferably, the detection reagent is specific for primers, probes and/or antibodies to the FMN1 gene or its expression product.
Wherein the treatment comprises at least one of inhibiting proliferation of tumor cells of the digestive tract, inhibiting migration of tumor cells of the digestive tract, inducing apoptosis of tumor cells of the digestive tract, or affecting metabolism of tumor cells of the digestive tract.
Wherein, in the application, the FMN1 gene is highly expressed in tumor cells of the digestive tract.
Wherein the expression product of the FMN1 gene is selected from the group consisting of cDNA, mRNA, FMN precursor protein, mature FMN1 protein and fragments thereof.
The invention also provides application of the expression inhibitor, the knockout reagent or the silencing reagent of the FMN1 gene in preparing medicines for preventing or treating digestive tract tumors.
Wherein the inhibitor of FMN1 gene expression comprises a drug that targets FMN1 and/or an agent that inhibits FMN1 expression.
Preferably, the FMN1 targeting drug is an antibody or a chemical drug directed against FMN 1.
Preferably, the agent that inhibits FMN1 expression comprises an agent that targets siRNA or Cas9 nuclease of FMN 1.
The invention also provides a composition of a medicament for preventing or treating digestive tract tumors, which comprises the expression inhibitor, the knockout reagent or the silencing reagent of the FMN1 gene and pharmaceutically acceptable auxiliary materials or auxiliary components.
Wherein the digestive tract tumor is KRAS mutant digestive tract tumor. Preferably, the digestive tract tumor comprises: intrahepatic cholangiocellular carcinoma, pancreatic cancer, colorectal cancer.
The FMN1 gene of the present invention may be also used as the prognosis marker of digestive tract tumor.
The beneficial effects are that: the invention utilizes a tissue chip to find that FMN1 is highly expressed in KRAS mutant digestive tract tumor, and utilizes a database to find that FMN1 is related to prognosis of KRAS mutant digestive tract tumor. The invention discovers that the knock-down FMN1 can inhibit migration and invasion of KRAS mutant digestive tract tumor cells, and achieves the effect of resisting tumor metastasis. Therefore, FMN1 can be used as a potential target point of KRAS mutant digestive tract tumor and as a development direction of KRAS mutant digestive tract tumor therapeutic drugs.
Drawings
FIG. 1 shows the risk factors for total and progression free survival of KRAS mutant gut tumors in the FMN1 database.
Fig. 2 is a schematic diagram showing that tcga+gtex flood cancer analysis shows that FMN1 is significantly higher expressed in a plurality of tumors such as COAD colon cancer, CHOL cholangiocarcinoma, PAAD pancreatic cancer, and the like than in normal tissues.
Fig. 3 is a schematic representation showing that FMN1 and KRAS expression are significantly positively correlated in TCGA databases (colorectal cancer, pancreatic cancer, intrahepatic cholangiocarcinoma).
FIG. 4 is a graph showing that knock-down FMN1 in example 1 is capable of inhibiting KRAS mutant gut tumor cell p-AKT (ser 473) signaling pathway.
Figure 5 schematic representation of the significant inhibition of KRAS mutant gut tumor cell invasion and migration by knockdown FMN1 in example 3.
Fig. 6 shows the results of the animal experiment in example 4: after 5-6 week old nude mice were intravenously injected with shCtrl and shFMN1 cells at 2 x 106panc-1, the pancreatic cancer cells injected with shFMN1 were observed on day 28, and lung metastasis of mice was significantly reduced compared to the shCtrl group (P < 0.01).
Detailed Description
Applicants' studies have found that aberrant expression of FMN1 is associated with KRAS mutated gut tumor prognosis, including intrahepatic cholangiocellular carcinoma, pancreatic cancer, colorectal cancer, and the like. The applicant's previous research finds that FMN1 is highly expressed in tumor cells and is related to KRAS mutant digestive tract tumor bad prognosis, however, the action mechanism of FMN1 involved in digestive tract tumorigenesis and development is not clear, and at present, there are few literature reports.
The applicant then found that FMN1 was expressed in a significant positive correlation with KRAS in the TCGA database (colorectal cancer: r2=0.27, p=5.4e-06; pancreatic cancer: r2=0.69, p=0; intrahepatic duct cancer: r2=0.58, p=2e-4), and in earlier experiments, invasion and migration of PANC1 (KRAS G12D), SW480 (KRAS G12V), loVo (KRAS G13D), MIA-PACA2 (KRAS G12C) could be significantly inhibited by lentiviral interference of FMN 1. In a mouse in vivo tail vein tumor cell injection metastasis model, knock-down FMN1 can significantly inhibit lung metastasis of PANC1 cells. The above results suggest that interference with FMN1 may inhibit the development of KRAS mutant gut tumor cells, potentially providing a molecular biological basis for the determination of the stage, pathological type, prognosis and prognosis of gut tumors.
The invention aims to provide a novel KRAS mutant digestive tract tumor treatment target. In particular to application of FMN1 gene or its expression product as target spot in preparing medicine for preventing or treating digestive tract tumor.
According to the invention, in TCGA database KRAS mutant digestive tract tumor, FMN1 high expression is found to be a risk factor of total survival and progression-free survival of patients, and further in TCGA combined GTX database, most tumors (including pancreatic cancer, colorectal cancer and intrahepatic bile duct cancer) are found, FMN1 is highly expressed in tumor tissues compared with normal tissues, and FMN1 and KRAS expression are obviously positively correlated, so that the applicant designs shFMN1 to knock down FMN1 protein of each KRAS mutant subtype digestive tract tumor cell line, in vitro experiments show that knock down FMN1 can reduce migration and invasion capacity of KRAS mutant tumor cell line, and in vivo experiments show that knock down FMN1 can obviously inhibit lung metastasis of PANC1 cells.
The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
RNAseq data (level 3) and corresponding clinical information for pancreatic and colorectal cancers were obtained from the cancer genomic map (TCGA) database (https:// portal. Gdc.com) as in FIG. 1. Statistical analysis was performed using R software v 4.0.3. The TCGA database found that FMN1 is a risk factor for total and progression free survival of KRAS mutant gut tumors. a-B) in the pancreatic cancer (KRAS mutation up to 90%) population, high FMN1 expression is a risk factor for overall survival and progression-free survival (HR 1.67.95% ci:1.10 to 2.52; HR 1.53% ci: 1.04-2.26); C-D) in the KRAS mutant CRC population, high expression of FMN1 is a risk factor for overall survival and progression-free survival (HR 1.44% CI:0.82-2.56; HR 1.45.95% CI: 0.90-2.32).
As shown in FIG. 2, TCGA+GTEx flood analysis shows that FMN1 is highly expressed in a plurality of tumors such as COAD, CHOL, PAAD compared with normal tissues. ( * P value <0.05; * P value <0.01; * P value <0.001 )
Experimental reagent
The PANC1 (KRAS G12D), SW480 (KRAS G12V), loVo (KRAS G13D), MIA-PACA2 (KRAS G12C) cell lines are derived from the cell bank of China academy of sciences (Shanghai, china). PANC1 cells were cultured in DMEM (Gibco, thermo Fisher) plus 10% fetal bovine serum (Gibco, thermo Fisher) and 1% penicillin-streptomycin solution, SW480 cells were cultured in L15 medium (Gibco, thermo Fisher) plus 10% fetal bovine serum (Gibco, thermo Fisher) and 1% penicillin-streptomycin solution, loVo cells were cultured in F12 medium (Gibco, thermo Fisher) plus 10% fetal bovine serum (Gibco, thermo Fisher) and 1% penicillin-streptomycin solution, MIA-PACA2 cells were cultured in DMEM medium (Gibco, thermo Fisher) plus 10% fetal bovine serum (Gibco, thermo Fisher), 2.5% horse serum (Bioshp, 209A) and 1% penicillin-streptomycin solution, 37℃and 5% CO 2 Cell incubator.
FMN1 knockdown shRNA lentiviruses were purchased from hantao, shFMN1 reference: pascale Monzo, michele Crestani, yuk Kien, et al adaptive mechanoproperties mediated by the formin FMN1 characterize glioblastoma fitness for invasion, dev cell 2021Oct 25;56 (20).
Antibody: FMN1 antibody (Cat: Q68DA 7) was purchased from abcepta, AKT1/2/3 antibody (Cat: T55561), P-AKT (Ser 473) antibody (Cat: T40067), beta-actin antibody from ABMART, P-AKT (Thr 308) (Cat: YP 0590) from Immunoway, and secondary antibody selected from horseradish peroxidase conjugated anti-rabbit antibody or anti-mouse antibody was purchased from ABMART.
As shown in fig. 3, FMN1 was expressed as a significant positive correlation with KRAS in TCGA databases (colorectal cancer, pancreatic cancer, intrahepatic cholangiocarcinoma). FMN1 was expressed as a significant positive correlation with KRAS in the TCGA database (colorectal cancer: r2=0.27, p=5.4 e-06; pancreatic cancer: r2=0.69, p=0; intrahepatic bile duct cancer: r2=0.58, p=2 e-4).
Example 1
shFMN1 lentivirus is constructed, the interference vector pHBLV-U6-MCS-EF1-Luc-T2A-Puro vector is selected, and the shRNA reference of the control viral vector is: pascale Monzo, michele Crestani, yuk Kien, et al adaptive mechanoproperties mediated by the formin FMN1 characterize glioblastoma fitness for invasion, dev cell 2021Oct 25;56 (20).
G, primer annealing to form double-stranded fragment with cohesive ends. And (3) carrying out enzyme digestion on the vector, connecting the interference fragment with the vector, and carrying out PCR identification on bacterial liquid after transformation.
Lentiviral packaging systems included the following plasmids: 1) A vector plasmid carrying shRNA; 2) A helper plasmid psPAX2 vector; 3) Helper plasmid pMD2G vector. 293T cells were passaged in advance for transfection. After the operation is finished, the mixture is placed at 37 ℃ and 5 percent CO 2 In the incubator of (2), the cell density was observed before transfection to reach 70-80% confluency, lipofection complex was mixed well and incubated at room temperature for 15min before being slowly added dropwise to 293T cells at 37℃with 5% CO 2 Culturing in a cell incubator; fresh complete medium containing 10% fetal bovine serum FBS was changed 16h after transfection; the virus supernatants were collected twice 48h and 72h after transfection, respectively. Centrifuging the virus supernatant at 4deg.C and 2000 Xg for 10min to remove cell debris; then collecting virus stock supernatant, placing in an overspeed centrifuge tube, centrifuging at 4deg.C, 82700 ×g for 120min, suspending virus precipitate in complete culture medium, packaging the super-separated heavy suspension in a sterilizing tube, and collecting lentivirus.
The well-conditioned PANC1 (KRAS G12D), SW480 (KRAS G12V), loVo (KRAS G13D), MIA-PACA2 (KRAS G12C) cell lines were seeded into 24-well plates at a cell concentration of 1X 105/ml, lentiviral infection was performed the next day, and 0.5ml Polybrene/medium mixture was added after removal of the medium.
Constructing stable transgenic strain, applying puromycin with final concentration range of 2-4 mug/ml, continuously treating lentivirus infected cells for 4 days, and detecting knock-down efficiency by using western blot.
In vitro culturing stable transgenic strain KRAS mutant digestive tract tumor cells PANC1 shCtrl, PANC1 shFMN1, SW480shCtrl, SW480 shFMN1, loVoshCtrl, loVoshFMN 1, MIA-PACA2 shCtrl and MIA-PACA2shFMN1, and performing western blot detection indexes FMN1, AKT, p-AKT (ser 473) and p-AKT (thr 308) expression. In vitro culturing stable transgenic strain KRAS mutant digestive tract tumor cells PANC1 shCtrl, PANC1 shFMN1, SW480shCtrl, SW480 shFMN1, loVoshCtrl, loVoshFMN 1, MIA-PACA2 shCtrl and MIA-PACA2shFMN1, collecting cells, adding protein lysate for lysis, determining protein concentration by BCA method, quantifying, performing SDS-PAGE electrophoresis, PVDF transfer, milk blocking, primary antibody (FMN 1, CDC42, AKT, p-AKT (Ser 473), p-AKT (Thr 308), incubating overnight at 4 ℃, secondary antibody incubation, and Chemidoc XRS software exposure.
As shown in fig. 4, western blot shows that FMN1 knockdown was achieved after infection with shFMN1 lentivirus, knocking down the p-AKT (ser 473) signaling pathway of FMN1 inhibited KRAS mutant gut tumors.
Example 2
The migration experiment is provided with a shCtrl control group and a shFMN1 knock-down group, the logarithmic growth phase is taken, starvation treatment is carried out on PANC1 shCtrl, PANC1 shFMN1, SW480shCtrl, SW480 shFMN1, loVoshCtrl, loVoshFMN 1, MIA-PACA2 shCtrl, MIA-PACA2shFMN1 cells before the experiment, PBS washing, trypsin digestion and collection are carried out, 250g centrifugation is carried out for 5min, supernatant is sucked, and cells are resuspended by a pre-heated serum-free medium, so that the cell density is regulated to 2X 105/mL. 600. Mu.L of complete medium containing 20% FBS was added to the lower chamber (i.e., 24-well plate bottom) plate and the chamber was placed in the plate; 200. Mu.L of the cell suspension was added to the transwell chamber and the culture was continued in the incubator for 24 hours. The chamber was carefully removed with forceps, the upper chamber liquid was blotted and transferred to a well where about 800. Mu.l of pre-chilled ethanol was pre-added and fixed at room temperature for 30min. Taking out the chamber, sucking up the fixing solution of the upper chamber and the lower chamber, adding a proper amount of 0.1% crystal violet dye solution, and dyeing for 30min at room temperature. The cells and dye solution on the surface of the bottom membrane of the upper chamber are carefully wiped off by a wet cotton stick, and the cells and dye solution are photographed and counted under a proper air-drying mirror after the cells and dye solution are gently washed with PBS for a plurality of times, the cells are taken out, and the liquid in the upper chamber is sucked.
Example 3
Transwell experiments were set up with KRAS mutant gut tumor cells shCtrl control and shFMN1 knockdown, a 5-fold diluted Matrigel was laid in the upper chamber of the Transwell chamber (8 um) and placed in an incubator for 20min. After it solidified, serum-free cell suspensions (about 1×105 cells, 200ul in volume) of PANC1 shCtrl, PANC1 shFMN1, SW480shCtrl, SW480 shFMN1, loVo shCtrl, loVo shFMN1, MIA-PACA2 shCtrl, MIA-PACA2shFMN1 cells were each added, and a medium containing 1% fetal bovine serum was added to the lower chamber and placed in an incubator. After 24h of culture, the cells were fixed on cold methanol ice, the cells at the bottom of the upper chamber hole were wiped off with a cotton swab, the cells at the bottom of the upper chamber were stained with crystal violet, and the invasiveness of tumor cells was observed under a microscope. BDmatrigel and pre-chilled serum-free medium at 4 ℃ are diluted in a ratio of 1:8, 80 mu L of the pre-chilled serum-free medium is sucked into an upper chamber of a transwell, the mixture is placed into an incubator for 5 hours to be incubated for drying into gel, a pore plate is taken out, 200 mu L of pre-warmed serum-free medium is added into the upper chamber, the mixture is kept stand for 30 minutes at room temperature, matrix gel is rehydrated, and residual culture solution is sucked. Cells in log phase and starved prior to the experiment were taken, washed with PBS, collected after trypsin digestion, centrifuged at 250g for 5min, the supernatant was aspirated, and the cells were resuspended in pre-warmed serum-free medium to adjust cell density to 2X 105/mL. Inoculating cells: 600. Mu.L of complete medium containing 20% FBS was added to the lower chamber plate, and the cells were placed in the plate and incubated in incubator for 48 hours. Carefully taking out the small chamber by using forceps, sucking up the liquid in the upper chamber, moving the liquid into a hole which is pre-added with about 800 mu L of pre-cooled ethanol, fixing the liquid at room temperature for 30min, taking out the small chamber, sucking up the fixing liquid in the upper chamber and the lower chamber, adding a proper amount of 0.1% crystal violet dye liquid, and dyeing the liquid at room temperature for 30min. The cells and the dye solution on the surface of the bottom membrane of the upper chamber are carefully rubbed by a wet cotton stick, and the cells and the dye solution are photographed and counted under a proper air-drying mirror after the cells and the dye solution are slightly washed and soaked for a plurality of times by PBS, the liquid in the upper chamber is sucked out.
As shown in fig. 5, the experimental results are as follows: transwell experiments found that knockdown FMN1 was able to inhibit invasion and migration of PANC1 (KRAS G12D), SW480 (KRAS G12V), loVo (KRAS G13D), MIA-PACA2 (KRAS G12C) cells.
Example 4
SPF-class BALB/C nude mice with age of 5-6 weeks are bred for 1 week and then are inoculated with cells, and illumination is performed for 12 hours per day, and brightness is alternated. Relative humidity 50% + -10%, temperature 23+ -2deg.C. Culturing in vitro cultured stable transgenic strain KRAS mutant digestive tract tumor cells PANC1 shCtrl and PANC1 shFMN1 in a cell culture bottle, taking logarithmic phase growth phase, performing conventional digestion on pancreatin, centrifuging for 5min at 250g, absorbing supernatant, cleaning cells with sterile physiological saline, centrifuging, enriching, repeating the above process for 3 times, re-suspending the cells with physiological saline, adjusting the cell concentration to 2×107 cells/ml, and collecting the cells in a centrifuge tube. 0.1ml of the cell suspension was taken for intravenous injection at the tail of each mouse. The cells were kept on the feed line, and mice were examined for lung metastasis on day 28 using a PerkinElmer IVIS Lumina III in vivo imaging system. Preparing 15mg/ml of fluorescein stock solution by using DPBS, filtering by using a 0.2um filter, injecting 150mg/kg of fluorescein into an abdominal cavity 10-15 minutes before living body imaging, placing a pre-anesthetized mouse into an imaging box, placing the head of the mouse into an anesthetic glass mask, clicking an acquisition button to obtain imaging pictures, naming and annotating the pictures in an Image Labels which automatically pop up to obtain the pictures, clicking an Image Adjust in the Tool pattern, clicking ROIs in the Tool pattern, selecting circles of the ROIs, clicking Measure ROIs, obtaining quantitative values of the ROI areas, and determining the quantitative units as Radiant Efficiency.
As shown in fig. 6, the animal experiment results show that the 5-6 week old nude tail is intravenous injected with 2 x 10 of shCtrl and shFMN1 6 After PANC-1 cells, on day 28, mice were significantly lower in lung metastasis by injection of shFMN1 pancreatic cancer cells than by injection of shCtrl group (P<0.01)。
The experimental results show that FMN1 knockdown can inhibit migration and invasion of KRAS mutant digestive tract tumor cells, plays a role in resisting tumor metastasis, and provides target supplement for KRAS mutant digestive tract tumor treatment.
Claims (10)
- The FMN1 gene or its expression product is used as target spot in preparing medicine for preventing and treating digestive tract tumor.
- 2. Use of an agent targeting the FMN1 gene or an expression product thereof in the manufacture of a medicament for the prevention or treatment of a digestive tract tumor.
- 3. The use according to claim 2, characterized in that: the agent targeting the FMN1 gene or its expression product is selected from the group consisting of: at least one of a nucleic acid, a polypeptide, a ribonucleoprotein complex, or a small molecule drug; preferably, the agent targeting the FMN1 gene or its expression product is selected from: at least one of antisense oligonucleotide, siRNA, dsRNA ribozyme, esiRNA, shRNA and small molecule drug.
- The application of FMN1 gene or its expression product as target spot in preparing medicine screening apparatus for preventing and treating digestive tract tumor.
- 5. The use according to claim 4, characterized in that: the drug screening device comprises a detection reagent for determining the level or activity of the FMN1 gene or its expression product; preferably, the detection reagent is specific for primers, probes and/or antibodies to the FMN1 gene or its expression product.
- 6. Use according to any one of claims 1-5, characterized in that: the expression product of the FMN1 gene is selected from at least one of cDNA, mRNA, FMN precursor protein, mature FMN1 protein and fragments thereof.
- Use of an inhibitor of fmn1 gene expression, a knockout agent or a silencing agent in the manufacture of a medicament for preventing or treating a digestive tract tumor.
- 8. The use according to claim 7, characterized in that: the expression inhibitor of the FMN1 gene comprises a drug targeting FMN1 and/or an agent inhibiting FMN1 expression; preferably, the FMN 1-targeting drug is an antibody or a chemical drug directed against FMN 1; preferably, the agent that inhibits FMN1 expression comprises an agent that targets siRNA or Cas9 nuclease of FMN 1.
- 9. A composition for preventing or treating digestive tract tumor, characterized in that: an expression inhibitor, knockout or silencing agent comprising the FMN1 gene of claim 7 or claim 8, and a pharmaceutically acceptable adjuvant or auxiliary ingredient.
- 10. The use according to any one of claims 1 to 8, or the composition according to claim 9, characterized in that: the digestive tract tumor is KRAS mutant digestive tract tumor; preferably, the digestive tract tumor comprises: intrahepatic cholangiocellular carcinoma, pancreatic cancer, colorectal cancer.
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