CN113817797A - Method for researching influence of lactic acid on lung cancer cell metastasis invasion capacity - Google Patents
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Abstract
本发明公开了一种研究乳酸影响肺癌细胞转移侵袭能力的方法，包括如下步骤：S1、验证乳酸诱导EMT表型更加明显；S2、验证Snail表达诱导EMT表型更加明显；S3、观察肺癌细胞H1299和A549经乳酸处理的EMT表型；S4、LKB1野生型的H1299的EMT表型明显、LKB1缺失型的A549的EMT表型不明显；S5、验证LKB1诱导了Snail表达；S6、推测过量乳酸影响了细胞内能量代谢的动态平衡；S7、推测LKB1可能通过调控下游激酶AMPK或者Src诱导了Snail表达；S8、验证AMPK磷酸化是因LKB1活性改变导致；S9、同时利用不同信号传导途径抑制剂，观察哪种信号通路抑制剂可影响乳酸对AMPK的磷酸化；S10、利用不同信号转导通路抑制剂筛选出介导LKB1调控Src激酶的信号通路。本方法能够阐明肿瘤转移的分子机制。
The invention discloses a method for studying the influence of lactic acid on the metastasis and invasion ability of lung cancer cells. The EMT phenotype of A549 and A549 treated with lactate; S4, LKB1 wild-type H1299 has obvious EMT phenotype, and LKB1-deficient A549 has no obvious EMT phenotype; S5, verify that LKB1 induces Snail expression; S6, speculate that excessive lactate affects The dynamic balance of intracellular energy metabolism; S7, it is speculated that LKB1 may induce the expression of Snail by regulating the downstream kinase AMPK or Src; S8, it is verified that the phosphorylation of AMPK is caused by the change of LKB1 activity; S9, using different signaling pathway inhibitors at the same time, To observe which signaling pathway inhibitor can affect the phosphorylation of AMPK by lactate; S10, use different signal transduction pathway inhibitors to screen out the signaling pathway mediating LKB1 regulation of Src kinase. This method can elucidate the molecular mechanism of tumor metastasis.
Description
Technical Field
The invention relates to the technical field of cell therapy, in particular to a method for researching the influence of lactic acid on the metastatic invasion capacity of lung cancer cells.
Background
The current relative 5-year survival rate of lung cancer is only 18%, and the main reason causing the low long-term survival rate of lung cancer patients is tumor invasion and metastasis, and researches show that about 80-90% of lung cancer death cases are caused by tumor metastasis, and the molecular mechanism of metastasis is not clear. In the existing research, the occurrence of lung cancer cell EMT is promoted by inducing transcription factor Snail through lactic acid which is an end product in tumor Warburg effect, so that invasion and metastasis are induced, and meanwhile, the relevant pathway of an energy metabolism key regulatory gene LKB1 is found to mediate the process of promoting the invasion and metastasis of the lung cancer cell through the Warburg effect.
In the prior art, a research method for the action and mechanism of a LKB 1-related channel in the process of mediating the Warburg effect to promote the invasion and metastasis of lung cancer cells is lacked, so that a key regulatory protein in the process cannot be screened and the function of the key regulatory protein can not be clarified, and a new molecular target and a new thought are provided for further clarifying the molecular mechanism of tumor metastasis and treating tumors.
Disclosure of Invention
The invention aims to provide a method for researching the influence of lactic acid on the metastatic invasion capacity of lung cancer cells, and aims to solve the technical problem that proteins participating in regulation and control of LKB 1-related pathways cannot be screened due to the lack of research on a mechanism of mediating the Warburg effect of the LKB 1-related pathways in the prior art.
In order to solve the technical problems, the invention specifically provides the following technical scheme,
a method for researching the influence of lactic acid on the metastatic invasiveness of lung cancer cells comprises the following steps:
s1, verifying that the EMT phenotype induced by lactic acid is more obvious by taking whether the EMT phenotype observed by the lung cancer cell is obvious as an index for judging the migration capacity and the invasion capacity of the lung cancer cell and placing the lung cancer cell in a lactic acid environment;
s2, presuming that lactic acid can promote expression of Snail in lung cancer cells, the expression of Snail induces EMT phenotype more obviously, and then observing whether the EMT phenotype is reversed or not by transfecting siRNA of Snail in lung cancer cell strains to verify that the expression of Snail induces the EMT phenotype more obviously;
s3, taking two in-vitro lung cancer cells H1299 and A549, respectively putting the H1299 and the A549 in lactic acid with the same concentration, inhibiting the lactic acid of the in-vitro lung cancer cells H1299 and A549 per se, and observing the EMT phenotype of the lung cancer cells H1299 and A549;
s4, according to the observation result of the step S3, the EMT phenotype of the LKB1 wild type H1299 is obvious, and the EMT phenotype of the LKB1 deletion type A549 is not obvious;
s5, presuming that lactic acid induces the Snail expression by controlling LKB1, knocking LKB1 out of H1299 by transferring cDNA of LKB1 into A549, and repeating the step S3 to verify that LKB1 induces the Snail expression;
s6, speculating that excess lactate affects the dynamic balance of energy metabolism within the cell, to provide LKB1 activity, or to cause LKB1 germline mutations;
s7, supposing that LKB1 can induce Snail expression by regulating downstream kinases AMPK or Src;
s8, knocking out LKB1 in H1299 cells, transferring cDNA of LKB1 in A549 cells, and verifying that AMPK phosphorylation is caused by change of LKB1 activity through a control test;
s9, observing which signal pathway inhibitors can influence phosphorylation of AMPK by lactic acid by using different signal transduction pathway inhibitors;
s10, transferring cDNA of LKB1 into an A549 cell with LKB1 deletion, transferring LKB1siRNA into an H1299 cell with LKB1 wild type, detecting the relation between LKB1 and Src kinase, and screening a signal path for mediating LKB1 to regulate Src kinase by using different signal transduction path inhibitors.
In a preferred embodiment of the present invention, in step S8, the control test comprises the steps of,
s801, the effect of lactic acid or hydrogen peroxide on LKB1 phosphorylation and AMPK phosphorylation in vitro lung cancer cells;
s802, transferring cDNA of LKB1 into A549, and treating the A549 according to the step S801;
s803, respectively transfecting the cDNA of the constructed SOD2 and mitochondrial catalase into lung cancer cells, and observing whether overexpression of the SOD2 and the mitochondrial catalase can influence the AMPK phosphorylation induced by lactic acid or hydrogen peroxide and the expression of Snail;
s804, knocking out LKB1 in H1299 cells; after the cDNA for LKB1 was transferred into a549 cells, and the cells were then treated using the method in step S803, it was confirmed that this p-AMPK was indeed derived from altered LKB1 activity.
Compared with the prior art, the invention has the following advantages,
the invention develops deep research through molecular and cell levels, discloses the function and mechanism of an LKB 1-related channel in the process of mediating the Warburg effect to promote the invasion and metastasis of lung cancer cells, can screen corresponding key regulatory proteins and clarify the functions of the key regulatory proteins, and provides a new molecular target and thought for further clarifying the molecular mechanism of tumor metastasis and treating tumors.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below. It should be apparent that the drawings in the following description are merely exemplary, and that other embodiments can be derived from the drawings provided by those of ordinary skill in the art without inventive effort.
FIG. 1 is a technical roadmap in an embodiment of the present invention;
FIG. 2 is a diagram illustrating the result of step S1 according to the embodiment of the present invention;
FIG. 3 is a diagram illustrating the result of step S2 according to the embodiment of the present invention;
fig. 4 is a graph showing the result of H1299 in step S3 according to the embodiment of the present invention;
fig. 5 is a graph showing the result of a549 in step S3 in the embodiment of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
As shown in figure 1, the invention provides a method for researching the metastatic invasive ability of a lung cancer cell influenced by lactic acid, which comprises the following steps:
s1, verifying that the EMT phenotype induced by lactic acid is more obvious by taking whether the EMT phenotype observed by the lung cancer cell is obvious as an index for judging the migration capacity and the invasion capacity of the lung cancer cell and placing the lung cancer cell in a lactic acid environment;
s2, presuming that lactic acid can promote expression of Snail in lung cancer cells, the expression of Snail induces EMT phenotype more obviously, and then observing whether the EMT phenotype is reversed or not by transfecting siRNA of Snail in lung cancer cell strains to verify that the expression of Snail induces the EMT phenotype more obviously;
s3, taking two in-vitro lung cancer cells H1299 and A549, respectively putting the H1299 and the A549 in lactic acid with the same concentration, inhibiting the lactic acid of the in-vitro lung cancer cells H1299 and A549 per se, and observing the EMT phenotype of the lung cancer cells H1299 and A549;
s4, according to the observation result of the step S3, the EMT phenotype of the LKB1 wild type H1299 is obvious, and the EMT phenotype of the LKB1 deletion type A549 is not obvious;
s5, presuming that lactic acid induces the Snail expression by controlling LKB1, knocking LKB1 out of H1299 by transferring cDNA of LKB1 into A549, and repeating the step S3 to verify that LKB1 induces the Snail expression;
s6, speculating that excess lactate affects the dynamic balance of energy metabolism within the cell, to provide LKB1 activity, or to cause LKB1 germline mutations;
s7, supposing that LKB1 can induce Snail expression by regulating downstream kinases AMPK or Src;
s8, knocking out LKB1 in H1299 cells, transferring cDNA of LKB1 in A549 cells, and verifying that AMPK phosphorylation is caused by change of LKB1 activity through a control test;
s9, observing which signal pathway inhibitors can influence phosphorylation of AMPK by lactic acid by using different signal transduction pathway inhibitors;
s10, transferring cDNA of LKB1 into an A549 cell with LKB1 deletion, transferring LKB1siRNA into an H1299 cell with LKB1 wild type, detecting the relation between LKB1 and Src kinase, and screening a signal path for mediating LKB1 to regulate Src kinase by using different signal transduction path inhibitors.
Exogenous lactic acid (with different concentrations) is used for treating lung cancer cell strains, the migration rate of cells is increased, the invasion capacity is enhanced, and the obvious influence of the lactic acid on the invasion and metastasis capacity of the lung cancer cell strains is proved. We also found that the Snail expression and EMT phenotype induced under high sugar culture conditions can be similarly reversed by both sirnas of lactate dehydrogenase. It is concluded that lactic acid, a metabolite in aerobic glycolysis, plays a key role in promoting the production of EMT by lung cancer cells, and is likely to play a role by inducing the transcription factor Snail. Subsequently, the lung cancer cell line is transfected with SnailsiRNA, and the induction of the EMT phenotype of the lung cancer cell by lactic acid is partially reversed, which proves that the lactic acid promotes the generation of the EMT of the lung cancer cell by inducing Snail.
The a549 and H1299 cell lines were treated with different concentrations of lactate, respectively, and lactate was found to promote expression of Snail and the EMT phenotype in the LKB1 wild-type H1299 cell line, but the lactate-induced EMT phenotype was not evident in LKB 1-deficient a 549. Extracellular lactate can enter cells through MCT1 transporter, and we found using siRNA of MCT1 inhibitor CHC and MCT1 that both partially reversed lactate-induced expression of Snail and EMT phenotype in lung cancer cells. It can be seen that the re-entry of lactic acid into the cell promotes the production of EMT by the lung cancer cell.
We found LKB1 to induce phosphorylation of Src inhibition site 527 in LKB 1-depleted a549 cells and NCI-H460 cells and LKB1shRNA in LKB1 wild-type H1299 cells, while LKB1siRNA promoted migration of H1299 cells under high sugar conditions was reversed by Src inhibitor PP 2. The results suggest that LKB1 may inhibit cell migration by modulating Src activity.
The invention develops deep research through molecular and cell levels, discloses the function and mechanism of an LKB 1-related channel in the process of mediating the Warburg effect to promote the invasion and metastasis of lung cancer cells, can screen corresponding key regulatory proteins and clarify the functions of the key regulatory proteins, and provides a new molecular target and thought for further clarifying the molecular mechanism of tumor metastasis and treating tumors.
In step S8, the control test includes the steps of,
s801, the effect of lactic acid or hydrogen peroxide on LKB1 phosphorylation and AMPK phosphorylation in vitro lung cancer cells;
s802, transferring cDNA of LKB1 into A549, and treating the A549 according to the step S801;
s803, respectively transfecting the cDNA of the constructed SOD2 and mitochondrial catalase into lung cancer cells, and observing whether overexpression of the SOD2 and the mitochondrial catalase can influence the AMPK phosphorylation induced by lactic acid or hydrogen peroxide and the expression of Snail;
s804, knocking out LKB1 in H1299 cells; after the cDNA for LKB1 was transferred into a549 cells, and the cells were then treated using the method in step S803, it was confirmed that this p-AMPK was indeed derived from altered LKB1 activity.
The above embodiments are only exemplary embodiments of the present application, and are not intended to limit the present application, and the protection scope of the present application is defined by the claims. Various modifications and equivalents may be made by those skilled in the art within the spirit and scope of the present application and such modifications and equivalents should also be considered to be within the scope of the present application.
Claims (2)
1. A method for researching the metastatic invasive ability of a lung cancer cell influenced by lactic acid is characterized by comprising the following steps:
s1, verifying that the EMT phenotype induced by lactic acid is more obvious by taking whether the EMT phenotype observed by the lung cancer cell is obvious as an index for judging the migration capacity and the invasion capacity of the lung cancer cell and placing the lung cancer cell in a lactic acid environment;
s2, presuming that lactic acid can promote expression of Snail in lung cancer cells, the expression of Snail induces EMT phenotype more obviously, and then observing whether the EMT phenotype is reversed or not by transfecting siRNA of Snail in lung cancer cell strains to verify that the expression of Snail induces the EMT phenotype more obviously;
s3, taking two in-vitro lung cancer cells H1299 and A549, respectively putting the H1299 and the A549 in lactic acid with the same concentration, inhibiting the lactic acid of the in-vitro lung cancer cells H1299 and A549 per se, and observing the EMT phenotype of the lung cancer cells H1299 and A549;
s4, according to the observation result of the step S3, the EMT phenotype of the LKB1 wild type H1299 is obvious, and the EMT phenotype of the LKB1 deletion type A549 is not obvious;
s5, presuming that lactic acid induces the Snail expression by controlling LKB1, knocking LKB1 out of H1299 by transferring cDNA of LKB1 into A549, and repeating the step S3 to verify that LKB1 induces the Snail expression;
s6, speculating that excess lactate affects the dynamic balance of energy metabolism within the cell, to provide LKB1 activity, or to cause LKB1 germline mutations;
s7, supposing that LKB1 can induce Snail expression by regulating downstream kinases AMPK or Src;
s8, knocking out LKB1 in H1299 cells, transferring cDNA of LKB1 in A549 cells, and verifying that AMPK phosphorylation is caused by change of LKB1 activity through a control test;
s9, observing which signal pathway inhibitors can influence phosphorylation of AMPK by lactic acid by using different signal transduction pathway inhibitors;
s10, transferring cDNA of LKB1 into an A549 cell with LKB1 deletion, transferring LKB1siRNA into an H1299 cell with LKB1 wild type, detecting the relation between LKB1 and Src kinase, and screening a signal path for mediating LKB1 to regulate Src kinase by using different signal transduction path inhibitors.
2. The method of claim 1, wherein the control test comprises the steps of S8,
s801, the effect of lactic acid or hydrogen peroxide on LKB1 phosphorylation and AMPK phosphorylation in vitro lung cancer cells;
s802, transferring cDNA of LKB1 into A549, and treating the A549 according to the step S801;
s803, respectively transfecting the cDNA of the constructed SOD2 and mitochondrial catalase into lung cancer cells, and observing whether overexpression of the SOD2 and the mitochondrial catalase can influence the AMPK phosphorylation induced by lactic acid or hydrogen peroxide and the expression of Snail;
s804, knocking out LKB1 in H1299 cells; after the cDNA for LKB1 was transferred into a549 cells, and the cells were then treated using the method in step S803, it was confirmed that this p-AMPK was indeed derived from altered LKB1 activity.
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| US20090226396A1 (en) * | 2008-03-07 | 2009-09-10 | Haley John D | Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation |
| WO2016011065A1 (en) * | 2014-07-15 | 2016-01-21 | Salk Institute For Biolofical Studies | Detecting dixdc1 (dix domain-containing protein 1) expression to determine if a tumor will respond to fak and src kinase inhibitors |
| CN108251526A (en) * | 2017-11-29 | 2018-07-06 | 南京医科大学 | The application of Suppressor of Cytokine Signaling 2 |
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| Title |
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| HUIJUN WEI ET AL.: "Upregulation of lactate-inducible snail protein suppresses oncogene-mediated senescence through p16INK4a inactivation", JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, 26 February 2018 (2018-02-26) * |
| 魏慧君: "乳酸诱导肺腺癌细胞上皮间质转化的机制研究", 中国优秀硕士学位论文全文数据库 医药卫生科技辑, 15 April 2016 (2016-04-15), pages 23 * |
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