CN115737813A - Application of LINC00205 inhibitor in preparation of medicine for treating liver cancer - Google Patents
Application of LINC00205 inhibitor in preparation of medicine for treating liver cancer Download PDFInfo
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Abstract
The invention provides an application of a LINC00205 inhibitor in preparing a medicament for treating liver cancer, wherein the LINC00205 inhibitor promotes apoptosis of liver cancer cells through an epigenetic regulation network, the epigenetic regulation network is a lactic acid metabolism network associated with ALDH5A1 gene, and the LINC00205 inhibitor regulates the ALDH5A1 gene in a targeted manner. The medicine is added with the LINC00205 inhibitor to inhibit the malignant problems of the aggravation of lactic acid metabolism imbalance in the liver cancer cells and the promotion of the invasion and the transfer of the liver cancer cells caused by the expression of the LINC00205, so that the medicine added with the LINC00205 inhibitor has the curative effect of treating the liver cancer.
Description
Technical Field
The invention relates to the technical field of tumor treatment medicines, in particular to application of a LINC00205 inhibitor in preparing a medicine for treating liver cancer.
Background
Hepatocellular carcinoma (HCC) is the most common pathological type in primary liver cancer, and is one of the most common malignant tumors worldwide. Although the current treatment strategies and methods for liver cancer have advanced sufficiently, the mortality rate of liver cancer still remains high, and the early detection and treatment of HCC become key factors influencing prognosis, so that the search for new diagnosis and treatment targets becomes the key for improving the early diagnosis rate and the survival rate after treatment of hepatocellular carcinoma patients. HCC onset is currently widely recognized as a gradual process involving multiple genes, multiple steps, and multiple stages. Metabolic reprogramming is one of the hallmark characteristics of malignant tumors, and due to the requirements of rapid proliferation, large energy consumption and the like of tumor cells, glucose metabolism by glycolysis is preferred to obtain the required energy. Local hypoxia (i.e. hypoxic microenvironment) of tumors caused by rapid proliferation of liver cancer is one of the special microenvironments of liver cancer cells, and under the hypoxic condition, anaerobic glycolysis becomes an important way for energy metabolism of tumor cells. Lactic acid is the final product of glucose anaerobic glycolysis, which creates an acidic Tumor Microenvironment (TME) that facilitates the selection of more aggressive tumor cells and promotes tumor development.
There is increasing evidence that lactic acid, as a tumor energy metabolite, not only plays a crucial role in maintaining tumorigenesis and progression and signal transduction in cancer, but also can remodel the tumor immune microenvironment and promote tumor progression by inducing and recruiting immune suppression-related cells and molecules. Macrophages are important innate immune cells in a tumor microenvironment, and can be differentiated into two phenotypes (M1 type and M2 type) in liver cancer due to different tumor microenvironments, generally, M1 type is considered to play a normal anti-inflammatory role and inhibit tumor progression; m2 type instead promotes tumor progression through mechanisms such as promotion of angiogenesis, suppression of local anti-tumor immunity, and the like. Lactic acid derived from tumor cells can induce the expression of Vascular Endothelial Growth Factor (VEGF) and arginase 1 (Arg 1) through an HIF 1-a signal pathway, promote the polarization of tumor-associated macrophages (TAM) to M2 type, and further promote the growth of tumors.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: preparing the medicine for treating liver cancer.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
application of LINC00205 inhibitor in preparing medicine for treating hepatocarcinoma is provided.
Further, the LINC00205 inhibitor promotes the apoptosis of the liver cancer cells through an epigenetic regulation network, the epigenetic regulation network is a lactic acid metabolism network associated with the ALDH5A1 gene, and the LINC00205 inhibitor controls the ALDH5A1 gene in a targeted mode.
Further, the LINC00205 inhibitor also reduces liver cancer cell migration through the epigenetic regulatory network.
Further, the LINC00205 inhibitor also reduces hepatoma cell invasion through the epigenetic regulatory network.
Further, the regulation of the ALDH5A1 gene comprises inhibiting the transcription of the ALDH5A1 gene or/and reducing the enzyme activity of ALDH5A1 lactate metabolizing enzyme.
Further, the transcription of the ALDH5A1 gene is the transcription of one or more segments of an ALDH6A1 gene segment, an IDH2 gene segment and an ME1 gene segment.
Further, the ALDH5A1 lactate metabolism enzyme is one or more of ALDH6A1, IDH2 and ME 1.
In the lactic acid metabolism network, the expression of Pan Kla protein in the hepatoma carcinoma cells is reduced, and the production of ATP and lactic acid in the hepatoma carcinoma cells is reduced.
Further, in the lactate metabolism network, the level of lactate-induced macrophage M2 polarization is reduced and the ability of angiogenesis in tumors is reduced.
Further, the LINC00205 inhibitor is one or two of LINC00205-siRNA-2 and LINC 00205-siRNA-3; the medicament containing the LINC00205 inhibitor is one of tablets, soft capsules, oral solutions and injections.
The invention has the beneficial effects that: the medicine is added with the LINC00205 inhibitor to inhibit the malignant problems of the aggravation of lactic acid metabolism imbalance in the liver cancer cells and the promotion of the invasion and the transfer of the liver cancer cells caused by the expression of the LINC00205, so that the medicine added with the LINC00205 inhibitor has the curative effect of treating the liver cancer.
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The detailed structure of the invention is described in detail below with reference to the accompanying drawings
FIG. 1 is the results of LINC01315, LINC-PVT1, LINC00482, LINC00205 and LINC00665 expression in paracancerous and cancer tissues (P <0.05 compared to paracancerous tissues);
FIG. 2 shows the localization of LINC00205 in hepatoma cells HepG2 and MHCC 97L;
figure 3 is the LINC00205 interference validation result (P <0.05 compared to control);
FIG. 4 shows the results of glucose affecting ATP and lactate metabolism in normal cells and knockdown LINC00205 cells (P <0.05 compared to control; P <0.05 compared to knockdown LINC00205 cells);
FIGS. 5 (A) and 5 (B) are the results of glucose influencing Pan Kla, panKac expression in normal cells and knocking down LINC00205 cells (P <0.05 compared to control; P <0.05 compared to knocking down LINC00205 cells);
FIG. 6 shows the results of 2-DG affecting the metabolism of ATP and lactate in normal cells and in knockdown LINC00205 cells (P <0.05 compared to control; P <0.05 compared to knockdown LINC00205 cells);
FIGS. 7 (A) and 7 (B) are the results of 2-DG affecting Pan Kla, panKac expression in normal cells and knockdown of LINC00205 cells (P <0.05 compared to control; P <0.05 compared to knockdown LINC00205 cells);
FIG. 8 shows the results of DCA, oxamate and Rotenone on the effects of ATP and lactate metabolism in normal cells and in knockdown of LINC00205 cells (P <0.05 compared to control; P <0.05 compared to knockdown of LINC00205 cells);
FIGS. 9 (A) and 9 (B) are the results of DCA, oxamate and Rotenone affecting Pan Kla, pan Kac expression in normal cells and knockdown of LINC00205 cells (P <0.05 compared to control group; P <0.05 compared to knockdown LINC00205 cells);
figure 10 is a graph of the effect of LINC00205 inhibitors on liver cancer cell viability (P <0.05 compared to control);
FIG. 11 shows the results of the effect of LINC00205 inhibitor on apoptosis of hepatoma cells (flow cytometry);
figure 12 is a graph of the effect of LINC00205 inhibitors on apoptosis of liver cancer cells (P <0.05 compared to control);
FIG. 13 is a graph showing the results of migration of LINC00205 inhibitor to HepG2 cells;
FIG. 14 is a graph showing the results of migration of MHCC97L cells by an inhibitor of LINC 00205;
figure 15 is a bar graph of the migration of LINC00205 inhibitors on HepG2 and MHCC97L cells (P <0.05 compared to control);
FIG. 16 is a graph showing the results of the invasion of HepG2 and MHCC97L cells by LINC00205 inhibitor;
figure 17 is a bar graph of the results of LINC00205 inhibitor invasion of HepG2 and MHCC97L cells (P <0.05 compared to control);
FIG. 18 is a graph of the results of F4/80+ CD206+ expression in LA treated BMDM and F4/80+ CD86+ expression in LPS treated BMDM (. +, P < 0.05);
FIG. 19 is a graph of the results of expression levels of LINC00205 in BMDM treated with LA or LPS (.;. P < 0.05;. P < 0.001);
FIG. 20 is a graph showing the effect of LA and ATP on the expression of LINC00205 in RAW264.7 cells;
FIG. 21 is a bar graph showing the effect of LA and ATP on the expression of LINC00205 in RAW264.7 cells (; P < 0.01;. P < 0.001);
FIG. 22 is a graph showing the results of localization of U6 snRNA and 18S rRNA in RAW264.7 cells;
FIG. 23 is a graph of the results of flow cytometry analysis of CD206+ expression in RAW264.7 cells after transfection with siRNA or control siRNA specifically targeting LINC00205 for 12 hours followed by 72 hours stimulation with LA or LPS (siCtr is silent group, si # 1 is LINC00205-siRNA-1, si # 2 is LINC 00205-siRNA-2);
FIG. 24 is a bar graph of CD206+ expression in RAW264.7 cells after 12 hr transfection with siRNA or control siRNA specifically targeting LINC00205 followed by 72 hr stimulation with LA or LPS (Ctrl is empty vector; #1 is LINC00205-siRNA-1; #2 is LINC00205-siRNA-2; # P <0.05 ns, no significant difference);
FIG. 25 is a graph showing the results of mRNA expression of M2 polarization marker gene in RAW264.7 cells (P < 0.05;. P < 0.01;. P <0.001 ns, no significant difference; si # 1 is LINC00205-siRNA-1; si # 2 is LINC 00205-siRNA-2);
FIG. 26 is a graph showing the results of CD206+ expression following LINC00205 overexpression in RAW264.7 cells treated with LA or ATP;
FIG. 27 is a graph showing the effect of LINC00205 on tumor cell migration (siCtr is silent group, si00205# 1 is LINC00205-siRNA-1, si00205# 2 is LINC 00205-siRNA-2);
FIG. 28 is a graph showing the effect of LINC00205 on tumor angiogenesis (siCtr is silent group, si00205# 1 is LINC00205-siRNA-1, and si00205# 2 is LINC 00205-siRNA-2);
FIG. 29 is a graph showing the effect of LINC00205 on functional macrophage-tumor cell crosstalk-a comparison of the number and size of tumors formed in mice of each group (shCtr is silent group, sh00205#1 is LINC00205-siRNA-1, and sh00205#2 is LINC 00205-siRNA-2);
FIG. 30 is a graph of the effect of LINC00205 on functional macrophage-tumor cell crosstalk, graph two-a graph comparing the weights of the tumors formed by the mice in each group (shCtr is the silent group, sh00205#1 is LINC00205-siRNA-1, and sh00205#2 is LINC 00205-siRNA-2);
FIG. 31 is a graph of the effect of LINC00205 on functional macrophage-tumor cell crosstalk, graph III-weight change of mice in each group (shCtr is silent group, sh00205# 1 is LINC00205-siRNA-1, and sh00205# 2 is LINC 00205-siRNA-2);
FIG. 32 is a graph of the effect of LINC00205 on functional macrophage-tumor cell crosstalk, four-the total tumor number change of tumors formed in mice of each group (shCtr is silent group, sh00205# 1 is LINC00205-siRNA-1, and sh00205# 2 is LINC 00205-siRNA-2);
FIG. 33 is the pathological staining result of tumor tissue and IHC image of CD206+ of each group of mice (shCtr is silent group, sh00205# 1 is LINC00205-siRNA-1, and sh00205# 2 is LINC 00205-siRNA-2);
figure 34 is a graph of the expression score of CD206+ in tumor tissue from each group of mice (. X., P < 0.001);
figure 35 is a graph of the results of qPCR assays for transfection efficiency of HEPG2 cells and SNU475 cells transfected with LINC00205 interference vector (# indicates P <0.05 compared to control and # indicates P <0.05 compared to NC);
fig. 36 is a graph of the results of qPCR assays for expression of lactate production-related proteins in transfected HEPG2 cells and SNU475 cells (# indicates P <0.05 compared to control and # indicates P <0.05 compared to NC);
fig. 37 (a) and 37 (B) are graphs showing the expression results of lactate production-related proteins in transfected HEPG2 cells (×) P <0.05 compared to control and # P <0.05 compared to NC;
fig. 38 (a) and 38 (B) are graphs showing the expression results of lactate production-related proteins in transfected SNU475 cells (×) vs. control P <0.05 and # vs. NC P < 0.05.
Detailed Description
1) Expression profile of LINC00205 in clinical specimens and tumor cell lines
Selecting 50 liver cancer patients treated by surgery in Shenzhen university Hospital, collecting cancer tissues and far-end paracancer tissue specimens, and storing at ultralow temperature for detection.
The expression levels of LINC01315, LINC-PVT1, LINC00482, LINC00205 and LINC00665 in cancer tissues and tissues beside the cancer tissues are respectively detected by adopting a qPCR method, data are recorded, a graph is drawn, and the result is shown in figure 1 in detail.
As can be seen from fig. 1, LINC01315, LINC-PVT1, LINC00482, LINC00205 and LINC00665 expression was significantly elevated in cancer tissues compared to paracancerous tissues with statistical significance of the differences (P < 0.05), where LINC00205 expression was found to be most significantly different and has a regulatory relationship with multiple lncrnas, i.e., LINC00205 was overexpressed in hepatocellular carcinoma tissues.
FISH sublocalization experiments were performed on LINC00205 expression and the results are detailed in FIG. 2.
As can be seen from fig. 2, LINC00205 is mainly expressed in the nucleus and cytoplasm of liver cancer cell HepG2 and liver cancer cell MHCC97L, and it is speculated that LINC00205 may participate in the regulation mechanism of liver cancer in various ways;
the interference verification test is respectively carried out on the liver cancer cell HepG2 and the liver cancer cell MHCC97L, and the test result is shown in figure 3 in detail.
As can be seen from the results of FIG. 3, the expression of LINC00205 was decreased in HepG2 by interference of LINC00205-siRNA-2 and LINC00205-siRNA-3, the difference being statistically significant (P < 0.05); wherein the reduction of the LINC00205-siRNA-2 group is more obvious; in MHCC97L, LINC00205-siRNA-2 has a reduced LINC00205 expression, the difference being statistically significant (P < 0.05).
In subsequent experiments, LINC00205-siRNA-2 was selected to knock down LINC00205 expression, as described above.
2) Effect of knockdown of LINC00205 expression on lactate metabolism
The concentrations of ATP and lactate produced by normal cells and knockdown LINC00205 expressing cells, respectively, were tested after treatment with different glucose concentrations (0 nM, 1nM, 5nM and 25 nM), and the results are detailed in fig. 4.
As can be seen from the results in fig. 4, ATP and lactate were both increased with increasing glucose concentration in both normal cells and in knockdown LINC00205 expressing cells, the difference was statistically significant (P < 0.05); compared with the normal cell group, the knocking-down of ATP and lactic acid generated by the LINC00205 cells is reduced, and the difference has statistical significance (P < 0.05).
After treatment with different glucose concentrations (0 nM, 1nM, 5nM and 25 nM), electrophoresis tests were performed on the expression of Histone H3 protein, the expression of Pan Kac protein and the expression of Pan Kla protein in normal cells and knockdown LINC00205 expression cells, respectively, and the results are detailed in FIG. 5 (A); specific expression profiles of Pan Kac protein expression and Pan Kla protein expression in normal cells and knockdown LINC00205 expressing cells, respectively, were tested after treatment with different glucose concentrations (0 nM, 1nM, 5nM, and 25 nM), and the results are detailed in fig. 5 (B).
As can be seen from fig. 5 (a) and 5 (B), there was no difference between the groups of Pan Kac protein expression in normal cells and knockdown LINC00205 cells, and Pan Kla protein expression increased with increasing glucose concentration, with the difference having statistical significance (P < 0.05); compared with the normal cell group, the expression of the Pan Kla protein of the cells is reduced after the expression of the LINC00205 is knocked down, and the difference is statistically significant (P < 0.05).
3) Effect of 2-DG (2-deoxy-D-glucose) on lactate metabolism in Normal cells and knockdown of LINC00205 cells
The concentrations of ATP and lactate produced in normal cells and knockdown LINC00205 expressing cells, respectively, were tested after treatment with different concentrations of 2-DG (0 nM, 1nM, 5nM and 25 nM) and the results are detailed in FIG. 6.
As can be seen in FIG. 6, ATP and lactate were both reduced in both normal and knockdown LINC00205 cells as the concentration of 2-DG was increased, with statistical significance for the difference (P < 0.05); compared with the normal cell group, the knocking-down LINC00205 cells have reduced ATP and lactic acid production, and the difference has statistical significance (P < 0.05).
Electrophoresis tests were performed on the expression of Histone H3 protein, the expression of Pan Kac protein and the expression of Pan Kla protein in normal cells and in knockdown LINC00205 expression cells, respectively, after treatment with different 2-DG concentrations (0 nM, 1nM, 5nM and 25 nM), and the results are detailed in FIG. 7 (A); specific expression profiles of Pan Kac protein expression and Pan Kla protein expression in normal cells and knockdown LINC00205 expressing cells, respectively, were tested after treatment with different 2-DG concentrations (0 nM, 1nM, 5nM, and 25 nM), and the results are detailed in FIG. 7 (B).
As can be seen from fig. 7 (a) and 7 (B), there was no difference in the expression of Pan Kac protein between the groups in normal cells and in knockdown LINC00205 cells, and the expression of Pan kla protein decreased with increasing concentration of 2-DG, with the difference having statistical significance (P < 0.05); compared with the normal cell group, the expression of Pan Kla protein of the LINC00205 cells is reduced, and the difference is statistically significant (P < 0.05).
4) Effect of DCA (sodium dichloroacetate), oxamate (sodium Oxamate) and Rotenone (mitochondrial Electron transport inhibitor) on lactate metabolism in Normal and knockdown LINC00205 cells
The concentrations of ATP and lactate generated in normal cells and knockdown LINC00205 expressing cells were tested after treatment with DCA, oxamate or Rotenone, respectively, and the results are detailed in fig. 8.
As can be seen from fig. 8, ATP and lactate generated after DCA and Oxamate treatment were both decreased and ATP and lactate generated after Rotenone treatment were both increased in normal cells and knockdown LINC00205 cells, with statistical significance for the difference (P < 0.05); compared with the normal cell group, the knocking-down of ATP and lactic acid generated by the LINC00205 cells is reduced, and the difference has statistical significance (P < 0.05).
After DCA, oxamate or Rotenone treatment, electrophoresis tests are respectively carried out on the Histone H3 protein expression, pan Kac protein expression and Pan Kla protein expression in normal cells and knockdown LINC00205 expression cells, and the results are detailed in figure 9 (A); the specific expression levels of PanKac protein expression and Pan Kla protein expression in normal cells and knockdown LINC00205 expressing cells, respectively, were tested after treatment with DCA, oxamate and Rotenone, and the results are detailed in FIG. 9 (B).
As can be seen from FIGS. 9 (A) and 9 (B), there was no difference between the groups of expression of Pan Kac protein in normal cells and knockdown LINC00205 cells, the expression of Pan Kla protein was decreased after DCA and Oxamate treatment, and the expression of Pan Kla protein was increased after Rotenone treatment, and the difference was statistically significant (P < 0.05).
5) Effect of knocking down LINC00205 expression on apoptosis and proliferation of liver cancer cells
The viability of HepG2 and MHCC97L cells was determined after treatment with siRNA-NC or LINC00205-siRNA, respectively, and the results are detailed in FIG. 10.
As can be seen in FIG. 10, the cell viability of the LINC00205-siRNA group was significantly reduced in HepG2 and MHCC97L cells compared to the control group, with the difference being statistically significant (P < 0.05).
After being treated by siRNA-NC or LINC00205-siRNA, the apoptosis of HepG2 and MHCC97L cells is respectively measured by a flow cytometer and bar graphs are drawn, the detection result of the flow cytometer is detailed in figure 11, and the result of the bar graphs is detailed in figure 12.
As can be seen in FIGS. 11 and 12, apoptosis of the LINC00205-siRNA group was significantly increased in HepG2 and MHCC97L cells, with the difference being statistically significant (P < 0.05).
6) Effect of knocking down LINC00205 expression on migration and invasion of liver cancer cells
Migration of HepG2 and MHCC97L cells was determined after treatment with siRNA-NC and LINC00205-siRNA, respectively, and the results are detailed in FIG. 13, FIG. 14 and FIG. 15.
As can be seen from fig. 13, 14 and 15, cell migration of the LINC00205-siRNA group was significantly reduced in HepG2 and MHCC97L cells compared to the control group, with the difference being statistically significant (P < 0.05).
After treatment with siRNA-NC and LINC00205-siRNA, the invasion of HepG2 and MHCC97L cells was determined, respectively, and the results are detailed in FIGS. 16 and 17.
As can be seen in FIGS. 16 and 17, cell invasion of the LINC00205-siRNA group was significantly reduced in HepG2 and MHCC97L cells, with the difference being statistically significant (P < 0.05).
7) Effect of LINC00205 on lactate-induced M2 polarization and Trans-modulation of CD206
To verify the specific expression of LINC00205 in M2 macrophages, BMDM was treated with LA or LPS for 72 hours and subjected to flow cytometric analysis to analyze the percentage of F4/80+ CD206+ or F4/80+ CD86+ cells, the results of which are detailed in FIG. 18. BMDM was treated with LA or LPS for 24 hours and analyzed by qRT-PCR for LINC00205 expression, the results are detailed in FIG. 19. As can be seen in fig. 18 and 19, LINC00205 was upregulated in LA-driven M2 polarization and decreased in BMDMs of LPDM (lipopolysaccharide-induced macrophages).
To better characterize the expression and subcellular localization of LINC00205, RAW264.7 cells were exposed to LA, ATP for indicated times (0 h, 48h, 72 h), respectively, and subjected to FISH analysis to test the expression of LINC00205, DAPI, and Merge, respectively, with the results detailed in fig. 20; the expression level of LINC00205 was further analyzed and the results are shown in FIG. 21. As can be seen from fig. 20 and 21, LINC00205 expression in RAW264.7 cells;
localization tests of U6 snRNA, 18S rRNA, DAPI and Merge were performed in RAW264.7 cells by FISH analysis, respectively, and the results are detailed in fig. 22. As can be seen from fig. 22, U6 snRNA exists in the nucleus and 18S rRNA exists in the cytoplasm, so U6 snRNA and 18S rRNA can be used as controls for localization.
RAW264.7 cells were transfected with siRNA specifically targeting LINC00205 or control siRNA for 12 hours, then stimulated with LA or LPS for 72 hours, and finally flow cytometric analysis and analysis of CD206+ percentage cells were performed, with results detailed in fig. 23 and fig. 24. As can be seen from FIGS. 23 and 24, the expression of CD206 in RAW264.7 cells was significantly reduced under the stimulation with LA and LPS.
mRNA of the M2 polarization marker gene in RAW264.7 cells was quantified by qRT-PCR and normalized to 18s rRNA expression, and the results are detailed in fig. 25. As can be seen in FIG. 25, qln-PCR results showed that the mRNA levels of the five M2 phenotypic markers (Fizz-1, PPAR- γ, MRC1, ARG1, and YM 1) were lower than the negative control group compared to the LINC00205 negative control group, i.e., LINC00205 was silenced in both RAW264.7 cells and BMDM.
The percent CD206+ expression cells in RAW264.7 cells treated with LA or ATP were analyzed by flow cytometry and the results are detailed in fig. 26. As can be seen in fig. 26, these CD206 positive cells were cleared after overexpression of LINC 00205.
As can be seen from the results of fig. 18 to fig. 26, LINC00205 is a potential incrna involved in M2 macrophage polarization, and both LA and ATP can significantly increase the expression of LINC00205 in RAW264.7 cells, the expression of LINC00205 being dominated by M2 polarization; upon silencing LINC00205, lactate-induced CD206+ expression in RAW264.7 cells was significantly reduced.
8) Effects of LINC00205 on tumor angiogenesis and tumor proliferation and migration promotion through lactic acid-induced M2 polarization
RAW264.7 cells were transfected with siRNA to obtain LINC00205, followed by LA or ATP induction for 48 hours. The medium was replaced with fresh medium without serum and the supernatant (supernatant referred to as CM) was collected after 24 hours. SKOV3 cells, a2780 cells and KHOS/NP cells were treated with CM in RAW264.7 cells for 24 hours and cell migration was assessed by Transwell analysis, with the results detailed in figure 27. As can be seen in FIG. 27, CM from LA or ATP treated RAW264.7 cells and BMDM increased the number of migratory cells in these cell lines, SKOV3 cells, A2780 cells and KHOS/NP cells.
HUVEC cells (SKOV 3 cells, A2780 cells and KHOS/NP cells described above) were seeded into a 96-well plate previously coated with Matrigel, and whether or not capillary-like structures could be formed was observed, and then the capillary-like structures were counted in the presence of different macrophage supernatants, and the results are shown in detail in FIG. 28. As can be seen in FIG. 28, CM from LA or ATP treated RAW264.7 cells significantly increased the number of lumen formations; in the LINC00205 knockdown group, the number of cavity formations per field of view was significantly reduced compared to the control group. I.e., knocking down LINC00205 affected the pro-angiogenic function of M2 macrophages. That is, inhibition of LINC00205 impairs angiogenesis of cancer cells induced by RAW264.7 cells.
RAW264.7 cells infected with LINC00205# 1, linc00205# 2 or control lentivirus were mixed with liver cancer HepG2 cells and implanted subcutaneously in mouse axilla for 6 weeks, 7 mice per group. The results of the size of the tumor formed in each group are shown in detail in FIG. 29, the results of the weight of the tumor formed in each group are shown in FIG. 30, the results of the weight change of the mice in each group are shown in FIG. 31, and the results of the number of individuals having tumors formed in the mice in each group are shown in FIG. 32. As can be seen from fig. 29 to 32, the growth of primary tumors was different after subcutaneous injection of the cell mixture between the control group and the LINC00205 knockout group compared to the control virus transduced cells, while the body weight of the mice was not changed; the vector group developed tumors first. That is, expression of LINC00205 promoted tumorigenesis. The pathological results and IHC image results of each group of tumor tissues were examined and the results are detailed in fig. 33. The expression score of CD206+ in tumor tissues was analyzed by Image-Pro Plus6.0 and the results are detailed in FIG. 34. As can be seen from fig. 33 and 34, less CD206+ was detected in the tumor region in the LINC00205 knockout group compared to the control group; when LINC00205 was knocked down, M2 macrophages were reduced.
9) The transfection efficiency of the LINC00205 interference vector transfected by HepG2 cells and SNU475 cells was verified by qPCR assay, and the results are detailed in fig. 35. As can be seen in FIG. 35, when the cells HepG2 and SNU475 were transfected with LINC00205-siRNA, LINC00205-siRNA-2 and LINC00205-siRNA-3 were both effective, with LINC00205-siRNA-3 being the most effective and the difference being statistically significant.
10 qPCR was used to detect the expression of lactate production-related proteins in HepG2 cells and SNU475 cells after transfection of LINC00205-siRNA-3, and the results are shown in FIG. 36. As can be seen from fig. 36, after the LINC00205 interference vector was transfected by HEPG2 cells, IDH2 expression in the LINC00205 interference group was significantly decreased compared to the blank control group and the empty load group, and the difference was statistically significant; after SNU475 cells are transfected with the LINC00205 interference vector, compared with a blank control group and an idle group, the ALDH6A1 and IDH2 expression of the LINC00205 interference group is obviously reduced, and the difference has statistical significance.
11 Westernblot was used to examine the expression of the lactate production-associated protein, and the results are shown in FIG. 37 (A), FIG. 37 (B), FIG. 38 (A) and FIG. 38 (B). As can be seen from fig. 37 (a), fig. 37 (B), fig. 38 (a) and fig. 38 (B), the expression of ALDH6A1, IDH2 and ME1 proteins in the LINC00205 interfering group was significantly decreased compared to the blank control group and the empty load group in the HEPG2 cells and SNU475 cells after LINC00205-siRNA-3 transfection, and the difference was statistically significant.
As is clear from the results in fig. 36, fig. 37 (a), fig. 37 (B), fig. 38 (a), and fig. 38 (B), the LINC00205 inhibitor controls the ALDH5A1 gene in a targeted manner, inhibits transcription of the ALDH5A1 gene, reduces the production amount of ALDH5A1 lactate metabolizing enzymes such as ALDH6A1, IDH2, and ME1, and further affects the expression level of Pan Kla protein.
In summary, the LINC00205 inhibitor added to the medicine for preparing the medicine for treating liver cancer provided by the invention regulates and controls the ALDH5A1 gene in a targeted manner, inhibits the transcription of the ALDH5A1 gene, reduces the generation amount and the enzyme activity of ALDH5A1 lactate metabolizing enzymes such as ALDH6A1, IDH2, ME1 and the like, further influences the expression level of Pan Kla protein, reduces the generation amount of ATP and lactate in liver cancer cells, reduces the level of lactate-induced macrophage M2 polarization and angiogenesis capacity, finally inhibits the malignant problems of aggravation imbalance of lactate metabolism in liver cancer cells, promotion of invasion and metastasis of liver cancer cells and promotion of liver cancer cell apoptosis due to LINC00205 expression.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes performed by the present specification and drawings, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (10)
- Application of LINC00205 inhibitor in preparing medicine for treating hepatocarcinoma is provided.
- 2. The use of the LINC00205 inhibitor for the preparation of a medicament for the treatment of liver cancer according to claim 1, wherein the LINC00205 inhibitor promotes apoptosis of liver cancer cells via an epigenetic regulatory network, the epigenetic regulatory network being a lactate metabolism network associated with the ALDH5A1 gene, the LINC00205 inhibitor targeting the ALDH5A1 gene.
- 3. The use of the LINC00205 inhibitor of claim 2 in the preparation of a medicament for treating liver cancer, wherein the LINC00205 inhibitor further reduces liver cancer cell migration through the epigenetic regulatory network.
- 4. The use of the LINC00205 inhibitor of claim 3 in the preparation of a medicament for the treatment of liver cancer, wherein the LINC00205 inhibitor further reduces liver cancer cell invasion through the epigenetic regulatory network.
- 5. The use of the LINC00205 inhibitor of any of claims 2 to 4, in the preparation of a medicament for the treatment of liver cancer, wherein the modulation of the ALDH5A1 gene comprises inhibiting transcription of the ALDH5A1 gene or/and reducing enzymatic activity of an ALDH5A1 lactate metabolizing enzyme.
- 6. The use of the LINC00205 inhibitor of claim 5, wherein the transcription of the ALDH5A1 gene is the transcription of one or more of an ALDH6A1 gene segment, an IDH2 gene segment, and an ME1 gene segment in the preparation of a medicament for the treatment of liver cancer.
- 7. The use of the LINC00205 inhibitor of claim 6 in the preparation of a medicament for the treatment of liver cancer, wherein said ALDH5A1 lactate metabolizing enzyme is one or more of ALDH6A1, IDH2, ME 1.
- 8. The use of the LINC00205 inhibitor of claim 7, in the preparation of a medicament for treating liver cancer, wherein expression of Pan Kla protein is decreased in a liver cancer cell and production of ATP and lactate is decreased in the liver cancer cell in the lactate metabolism network.
- 9. The use of the inhibitor of LINC00205 in the manufacture of a medicament for the treatment of liver cancer according to claim 8, wherein the lactate metabolic network has a decreased level of lactate-induced macrophage M2 polarization and a decreased ability to angiogenesis in a tumor.
- 10. The use of the LINC00205 inhibitor according to any of claims 6 to 9 in the manufacture of a medicament for the treatment of liver cancer, wherein the LINC00205 inhibitor is one or both of LINC00205-siRNA-2 and LINC 00205-siRNA-3; the medicament containing the LINC00205 inhibitor is one of tablets, soft capsules, oral solutions and injections.
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