Bioinformatics Analysis Revealed Potential Tumor Suppressors (KLF4/CGN), Oncogenes (SHH/LIF) and Biomarkers of Asian Stomach Adenocarcinoma

Stomach adenocarcinoma (STAD) is the fifth most prevalent cancer and the third leading cause of cancer-related death in the world and is more common in Asia than in most Western countries. There is an urgent need to identify potential novel oncogenes and tumor suppressor genes, and biomarkers for STAD. 6652 differentially expressed genes were identified between STAD and normal samples based on the transcriptome data analysis of the TCGA and GEO databases. 13 key modules were identified in STAD by WGCNA analysis. 293 potential STAD associated genes were identified from intersection by Venn Diagram. The 293 intersected genes were enriched in cell cortex and infection by GO and KEGG analysis. 10 hub genes were identified from PPI and Cytoscape analyses of the intersected genes. KLF4/CGN low and SHH/LIF high expression were associated with short overall survival of Asian STAD patients. Bioinformatics analysis revealed potential novel tumor suppressors (KLF4/CGN), oncogenes (SHH/LIF) and biomarkers for diagnosis, therapy and prognosis of STAD, specifically for Asian patients.

Identification of reference genes provides functional insights into meiotic recombination suppressors in Gerbera hybrida

Gerbera Hybrida is one of the important cut flowers across the world.The novel traits are the primarily market requirements and the breeding targets,mainly determined by the degree of genetic variation after hybridization.However,meiotic recombination is highly conserved in most eukaryotes which suppressed the crossover formation and limited the genetic diversity.Recently,several meiotic recombination suppressors have been identified and characterized in plants,whereas it remains elusive in G.hybrida.In order to characterize the expression patterns of these suppressors in G.hybrida,20 candidate reference genes were identified from the transcriptome datasets of G.hybrida,and their expression stabilities during plant development were evaluated by geNorm,NormFinder and BestKeeper.Although the most stable reference genes were variable in different softwares,comprehensive ranking revealed that PGK2 was the most stable reference gene and GAPDH was the most unstable one.The expression patterns of FANCM,FIGL1,RECQ4,RM1,and FLIP further validated that PGK2 was suitable for normalization of gene expression.Our study identified a reliable reference gene for gene expression during meiotic recombination,and provided functional insights into meiotic recombination suppressors in G.hybrida.

Silencing suppressors:viral weapons for countering host cell defenses

RNA silencing is a conserved eukaryotic pathway involved in the suppression of gene expression via sequence-specific interactions that are mediated by 21–23 nt RNA molecules.During infection,RNAi can act as an innate immune system to defend against viruses.As a counter-defensive strategy,silencing suppressors are encoded by viruses to inhibit various stages of the silencing process.These suppressors are diverse in sequence and structure and act via different mechanisms.In this review,we discuss whether RNAi is a defensive strategy in mammalian host cells and whether silencing suppressors can be encoded by mammalian viruses.We also review the modes of action proposed for some silencing suppressors.

DNA methylation profiles in cancer:functions,therapy,and beyond

DNA methylation in cancer DNA methylation,a reversible post-replication modification,defines gene expression and function in different physiologic processes.Hypomethylation is quite common among global DNA modifications,while promoter hypermethylation often occurs in local regions during cancer,as in CpG island formation,thereby perpetuating the inactivation of tumor suppressor genes.

LATS1 Promotes B-ALL Tumorigenesis by Regulating YAP1 Phosphorylation and Subcellular Localization

Objective YAP1 plays a dual role as an oncogene and tumor suppressor gene in several tumors;differentiating between these roles may depend on the YAP1 phosphorylation pattern.The specific function of YAP1 in B cell acute lymphoblastic leukemia(B-ALL),however,is currently unclear.Thus,in the present study,the role of YAP1 in B-ALL was investigated using relevant cell lines and patient datasets.Methods The effects of shRNA-mediated knockdown on YAP1 and LATS1 levels in the NALM6 and MOLT-4 cell lines were examined using Western blotting,quantitative real-time polymerase chain reaction,flow cytometry,immunostaining,and nude mouse subcutaneous tumorigenesis experiments.Gene expression levels of Hippo pathway-related molecules before and after verteporfin(VP)treatment were compared using RNA-Seq to identify significant Hippo pathway-related genes in NALM6 cells.Results Patients with ALL showing high YAP1 expression and low YAP1-Ser127 phosphorylation levels had worse prognoses than those with low YAP1 protein expression and high YAP1-Ser127 phosphorylation levels.YAP1-Ser127 phosphorylation levels were lower in NALM6 cells than in MOLT-4 and control cells;YAP1 was distributed in the nuclei in NALM6 cells.Knockdown of YAP1 inhibited MOLT-4 and NALM6 cell proliferation and arrested the NALM6 cell cycle in the G0/G1 phase.Before and after VP treatment,the expression of the upstream gene LATS1 was upregulated;its overexpression promoted YAP1-Ser127 phosphorylation.Further,YAP1 was distributed in the plasma.Conclusion LATS1 may downregulate YAP1-Ser127 phosphorylation and maintain B-ALL cell function;thus,VP,which targets this axis,may serve as a new therapeutic method for improving the outcomes for B-ALL patients.

miR-30a-5p/PHTF2 axis regulates the tumorigenesis and metastasis of lung adenocarcinoma

Background:Lung adenocarcinoma is a very pervasive histological form of lung cancers,and inhibiting metastasis is crucial for effective treatment.In this investigation,we explored the functional interaction of miR-30a-5p and the putative transcription factor 2 of the homeodomain(PHTF2)in dictating the aggressiveness and metastasis of lung adenocarcinoma.Method:We collected clinical samples to evaluate the expression patterns of miR-30a-5p and PHTF2 in lung adenocarcinoma along with normal tissues.Cellular experiments including cell count kit(CCK)-8 growth assay,apoptosis analysis,migration and invasion examinations were performed to assess the aggressiveness of lung adenocarcinoma cells.Furthermore,we examined tumorigenesis and metastasis in a nude mouse model.Results:MiR-30a-5p exhibited downregulation pattern in lung adenocarcinoma samples.Transfection of miR-30a-5p mimic in lung adenocarcinoma cells resulted in the suppression of malignant characteristics.Notably,the administration of miR-30a-5p mimic also curbed tumorigenesis and metastasis of lung adenocarcinoma cells in animal model.Moreover,PHTF2 was found to be a molecular target of miR-30a-5p.Upregulating PHTF2 counteracted the tumor-suppressive effect of the miR-30a-5p mimic.Conclusion:miR-30a-5p functions as a tumor-suppressive molecule while PHTF2 acts as an oncogenic factor in the development and metastasis of lung adenocarcinoma.Therefore,targeting miR-30a-5p and PHTF2 could be developed into a promising therapeutic approach for inhibiting metastasis in lung adenocarcinoma.

Mechanisms of myeloid-derived suppressor cell-mediated immunosuppression in colorectal cancer and related therapies

Severe immunosuppression is a hallmark of colorectal cancer(CRC).Myeloid-derived suppressor cells(MDSCs),one of the most abundant components of the tumor stroma,play an important role in the invasion,metastasis,and immune escape of CRC.MDSCs create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells,including T and natural killer cells,as well as by inducing the proliferation of immunosuppressive cells,such as regulatory T cells and tumor-associated macrophages,which,in turn,promote the growth of cancer cells.Thus,MDSCs are key contributors to the emergence of an immunosup-pressive microenvironment in CRC and play an important role in the breakdown of antitumor immunity.In this narrative review,we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment,the current therapeutic approaches and technologies targeting MDSCs,and the therapeutic potential of modulating MDSCs in CRC treatment.This study provides ideas and methods to enhance survival rates in patients with CRC.

Intermittent fasting boosts antitumor immunity by restricting CD11b^(+)Ly6C^(low)Ly6G^(low) cell viability through glucose metabolism in murine breast tumor model

Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed that two cycles of fasting treatment significantly inhibited breast tumor growth and lung tissue metastasis,as well as prolonged overall survival in mice bearing 4T1 and 4T07 breast cancer.During this process,both the immunosuppressive monocytic-(M-)and granulocytic-(G-)myeloid-derived suppressor cell(MDSC)decreased,accompanied by an increase in interleukin(IL)7R^(+)and granzyme B^(+)T cells in the tumor microenvironment.Interestingly,we observed that Ly6G^(low)G-MDSC sharply decreased after fasting treatment,and the cell surface markers and protein mass spectrometry data showed potential therapeutic targets.Mechanistic investigation revealed that glucose metabolism restriction suppressed the splenic granulocytemonocyte progenitor and the generation of colony-stimulating factors and IL-6,which both contributed to the accumulation of G-MDSC.On the other hand,glucose metabolism restriction can directly induce the apoptosis of Ly6G^(low)G-MDSC,but not Ly6G^(high)subsets.In summary,these results suggest that glucose metabolism restriction induced by fasting treatment attenuates the immune-suppressive milieu and enhances the activation of CD3^(+)T cells,providing potential solutions for enhancing immune-based cancer interventions.

A new perspective on immune evasion:escaping immune surveillance by inactivating tumor suppressors

Inactivating mutations in tumor suppressor genes(TSGs)are known to drive tumorigenesis by decoupling proliferation and survival from tight regulatory mechanisms.In a recent study published in Science,Martin et al.1 shed light on an unappreciated role of TSGs in preventing immune evasion by demonstrating enrichment of TSG inactivation in tumor cell transplants in mice when facing an intact adaptive immune system.

Single-cell transcriptome profiling of sepsis identifies HLA-DR^(low)S100A^(high)monocytes with immunosuppressive function

Background Sustained yet intractable immunosuppression is commonly observed in septic patients,resulting in aggravated clinical outcomes.However,due to the substantial heterogeneity within septic patients,precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking.Methods We adopted cross-species,single-cell RNA sequencing(scRNA-seq)analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis.Flow cytometry,laser scanning confocal microscopy(LSCM)imaging and Western blotting were applied to identify the presence of S100A9^(+)monocytes at protein level.To interrogate the immunosuppressive function of this subset,splenic monocytes isolated from septic wild-type or S100a9^(–/–)mice were co-cultured with naive CD4^(+)T cells,followed by proliferative assay.Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage.Results scRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis,for which distinct monocyte subsets were enriched in disparate subclusters of septic patients.We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR(HLA-DR),which were prominently enriched in septic patients and might exert immunosuppressive function.By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments,we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice,corresponding to HLA-DR^(low)S100A^(high)monocytes in human sepsis.Moreover,we found that S100A9^(+)monocytes exhibited profound immunosuppressive function on CD4^(+)T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression.Conclusions This study identifies HLA-DR^(low)S100A^(high)monocytes correlated with immunosuppressive state upon septic challenge,inhibition of which can markedly mitigate sepsis-induced immune depression,thereby providing a novel therapeutic strategy for the management of sepsis.

Role of p53 suppression in the pathogenesis of hepatocellular carcinoma

In the world,hepatocellular carcinoma(HCC)is among the top 10 most prevalent malignancies.HCC formation has indeed been linked to numerous etiological factors,including alcohol usage,hepatitis viruses and liver cirrhosis.Among the most prevalent defects in a wide range of tumours,notably HCC,is the silencing of the p53 tumour suppressor gene.The control of the cell cycle and the preservation of gene function are both critically important functions of p53.In order to pinpoint the core mechanisms of HCC and find more efficient treatments,molecular research employing HCC tissues has been the main focus.Stimulated p53 triggers necessary reactions that achieve cell cycle arrest,genetic stability,DNA repair and the elimination of DNA-damaged cells’responses to biological stressors(like oncogenes or DNA damage).To the contrary hand,the oncogene protein of the murine double minute 2(MDM2)is a significant biological inhibitor of p53.MDM2 causes p53 protein degradation,which in turn adversely controls p53 function.Despite carrying wt-p53,the majority of HCCs show abnormalities in the p53-expressed apoptotic pathway.High p53 in-vivo expression might have two clinical impacts on HCC:(1)Increased levels of exogenous p53 protein cause tumour cells to undergo apoptosis by preventing cell growth through a number of biological pathways;and(2)Exogenous p53 makes HCC susceptible to various anticancer drugs.This review describes the functions and primary mechanisms of p53 in pathological mechanism,chemoresistance and therapeutic mechanisms of HCC.

Heat shock factor 1 promotes neurite outgrowth and suppresses inflammation in the severed spinal cord of geckos

The low intrinsic growth capacity of neurons and an injury-induced inhibitory milieu are major contributo rs to the failure of sensory and motor functional recovery following spinal cord injury.Heat shock transcription factor 1(HSF1),a master regulator of the heat shock response,plays neurogenetic and neuroprotective roles in the damaged or diseased central nervous system.However,the underlying mechanism has not been fully elucidated.In the present study,we used a gecko model of spontaneous nerve regeneration to investigate the potential roles of gecko HSF1(gHSF1) in the regulation of neurite outgrowth and inflammatory inhibition of macrophages following spinal cord injury.gHSF1 expression in neurons and microglia at the lesion site increased dramatically immediately after tail amputation.gHSF1 ove rexpression in gecko primary neuro ns significantly promoted axonal growth by suppressing the expression of suppressor of cytokine signaling-3,and fa cilitated neuro nal survival via activation of the mitogen-activated extracellular signal-regulated kinase/extracellular regulated protein kinases and phosphatidylinositol 3-kinase/protein kinase B pathways.Furthermore,gHSF1 efficiently inhibited the macrophagemediated inflammatory response by inactivating 1kappa B-alpha/NF-kappaB signaling.Our findings show that HSF1 plays dual roles in promoting axonal regrowth and inhibiting leukocyte inflammation,and provide new avenues of investigation for promoting spinal co rd injury repair in mammals.

The role of targeting protein for Xklp2 in tumorigenesis of hepatocellular carcinoma

To the Editor:Hepatocellular carcinoma(HCC)is a prevalent form of gastrointestinal malignancies.The current combination of immunotherapy and other treatments improves overall survival compared to conventional therapies,but the immunosuppressive microenvironment of HCC is a significant barrier to the efficacy of immunothera-peutic drugs[1].Tumor immune escape is promoted by interactions among immunosuppressive cells,including tumor-associated macrophages,marrow-derived suppressor cells,tumor-associated neutrophils,cancer-associated fibroblasts,and tumor-infiltrating Tregs[2].

Mobilization of monocytic myeloid-derived suppressor cells is regulated by PTH1R activation in bone marrow stromal cells

Myeloid-derived suppressor cells(MDSCs)are bone marrow(BM)-derived immunosuppressive cells in the tumor microenvironment,but the mechanism of MDSC mobilization from the BM remains unclear.We investigated how BM stromal cell activation by PTH1R contributes to MDSC mobilization.PTH1R activation by parathyroid hormone(PTH)or PTH-related peptide(PTHrP),a tumor-derived counterpart,mobilized monocytic(M-)MDSCs from murine BM without increasing immunosuppressive activity.In vitro cell-binding assays demonstrated thatα4β1 integrin and vascular cell adhesion molecule(VCAM)-1,expressed on M-MDSCs and osteoblasts,respectively,are key to M-MDSC binding to osteoblasts.Upon PTH1R activation,osteoblasts express VEGF-A and IL6,leading to Src family kinase phosphorylation in M-MDSCs.Src inhibitors suppressed PTHrP-induced MDSC mobilization,and Src activation in M-MDSCs upregulated two proteases,ADAM-17 and MMP7,leading to VCAM1 shedding and subsequent disruption of M-MDSC tethering to osteoblasts.Collectively,our data provide the molecular mechanism of M-MDSC mobilization in the bones of tumor hosts.

RASAL2 acts as a tumor suppressor in cervical cancer cells

This study was designed to investigate the roles of RASAL2 in cervical cancer(CC).Methods:Fifty-four CC tissues and 33 adjacent tissues were obtained from CC patients admitted to our hospital between March 2012 and June 2014.Real-time polymerase chain reaction and western blotting were performed to analyze the expression of RASAL2 mRNA and protein in these tissues,CC cell lines,and normal cervical cells.Over-expression and silencing of RASAL2 were induced after transfection,and the migration,invasion,and proliferation of the CC cell lines were examined.Results:RASAL2 mRNA and protein expressions were significantly down-regulated in CC tissues and cell lines than in adjacent tissues and normal cervical cells,respectively.While low RASAL2 expression correlated with advanced stage and metastasis of CC,its over-expression significantly inhibited proliferation and metastasis of CC cells and induced apoptosis.Under in vitro conditions,silencing of RASAL2 expression could significantly increase the proliferation,invasion,and migration of CC cells.Conclusion:RASAL2 functioned as a tumor suppressor in CC,and was down-regulated in CC tissue samples and cell lines.

Radiation-Induced Chromosome Instability in WTK1 and TK6 Human Lymphoblastoid Cells

The effects of ionizing radiation on single nucleotide polymorphism (SNP) copy number variations between TK6 and WTK1 cell lines are described herein. Specifically, the integrity of the chromosomes for two WIL2-derived lymphoblastoid cell lines (TK6 and WTK1) was analyzed in the presence and absence of ionizing radiation. WTK1 cells contain a p53 mutation, whereas the TK6 cell line has the native p53 tumor-suppressor gene. Each cell line was isolated post-irradiation for SNP analysis, which showed significant, genome-wide impacts on both cell lines;for the mutant WTK1 sample, there were a total of 48 gene deletions and no gene amplifications, whereas for the wild-type TK6 sample, there were 217 gene deletions and 9 gene amplifications. It appears that both cell lines are affected in the areas of cell-cycle control, but that other affected areas differ significantly between the two.

Comprehensive analysis of cell-extracellular matrix protein Ras suppressor-1 in function and prognosis of gastrointestinal cancers

BACKGROUND Ras suppressor 1(RSU1),a highly conserved protein,plays an important role in actin cytoskeleton remodeling and cell-extracellular matrix adhesion.Aberration of RSU1 activity can cause changes in cell adhesion and migration,thereby enhancing tumor proliferation and metastasis.However,the correlation between RSU1 and gastrointestinal cancers(GICs),as well as its prognostic role related to tumor-infiltrating immune cells(TIICs)remains unclear.AIM To shows RSU1 plays a potential promoting role in facilitating tumor immune escape in GIC.METHODS Differential expression of RSU1 in different tumors and their corresponding normal tissues was evaluated by exploring the Gene Expression Profiling Interactive Analysis(GEPIA)dataset.The correlation between RSU1 expression and prognosis of GIC cancer patients was evaluated by Kaplan-Meier plotter.Then,RSU1-correlated genes were screened and functionally characterized via enrichment analysis.The correlation between RSU1 and TIICs was further characterized using the Tumor Immune Estimation Resource(TIMER).In addition,the correlation between RSU1 and immune cell surface molecules was also analyzed by TIMER.RESULTS High RSU1 expression was associated with poor overall survival of gastric cancer patients,exhibiting a hazard ratio(HR)=1.36,first progression HR=1.53,and post progression survival HR=1.6.Specifically,high RSU1 Levels were associated with prognosis of gastric cancer in females,T4 and N3 stages,and Her-2-negative subtypes.Regarding immune-infiltrating cells,RSU1 expression level was positively correlated with infiltration of CD4+T cells,macrophages,neutrophils,and dendritic cells(DCs)in colorectal adenocarcinoma and stomach adenocarcinoma.RSU1 expression was also predicted to be strongly correlated with immune marker sets in M2 macrophage,DCs and T cell exhaustion in GICs.CONCLUSION In gastrointestinal cancers,RSU1 is increased in tumor tissues,and predicts poor survival of patients.Increased RSU1 may be involved in promoting macrophage polarization,DC infiltration,and T cell exhaustion,inducing tumor immune escape and the development of tumors in GICs.We suggest that RSU1 is a promising prognostic biomarker reflecting immune infiltration level of GICs,as well as a potential therapeutic target for precision treatment through improving the immune response.

A Study of Radiation-Induced Instability for the Gene Locus Associated with Intellectual Disorders or Developmental Delays

Multiplex Ligation-Dependent Probe Amplification (MLPA) was used to study the integrity of the chromosomes for two WIL2-derived lymphoblastoid cell lines (TK6 and WTK1) in the presence and absence of ionizing radiation. WTK1 cells contain a p53 mutation, whereas the TK6 cell line has the native p53 tumor-suppressor gene. Each cell line was isolated pre- and post-irradiation (2 and 3 Gy) and analyzed by MLPA. Using probes that target specific regions on chromosomes associated with a distinct subset of microdeletions and microduplications either established or thought to be responsible for intellectual disability or developmental delay, we have demonstrated that WTK1 and TK6 are not impacted in the same way by irradiation. Instead, each cell line presents its own unique MLPA profile. The most notable differences are the appearance of nine unique probe signals only seen in WTK1 cells. These results are important in the study of how different cell lines can be affected in significantly different ways depending on the presence or absence of wild type p53.

MTSS1在非小细胞肺癌中的表达及临床意义

目的探讨转移抑制因子1(MTSS1)在非小细胞肺癌(NSCLC)发生发展中的作用及临床价值。方法收集本院2006年3月至2008年3月存档的98例NSCLC石蜡标本,构建组织芯片并采用免疫组织化学法检测98例NSCLC组织及对应癌旁组织中MTSS1的表达,分析其与临床病理参数(年龄、性别、淋巴结转移、病理类型、分化程度和TNM分期)的关系;随访不同MTSS1表达者的生存情况;构建pcDNA3.1-MTSS1表达载体(pcDNA3.1-MTSS1组)和pcDNA3.1空载体(pcDNA3.1组)并分别转染肺癌A549细胞,采用Western blotting法检测两组MTSS1的蛋白水平,采用四甲基偶氮唑盐MTT法和划痕试验检测两组细胞的增殖与迁移情况。结果癌组织中MTSS1阳性表达率低于癌旁组织(56.1%vs.100.0%;P<0.05),MTSS1的表达与性别、年龄、分化程度和病理类型均无关,而与淋巴结转移和TNM分期有关(P<0.05);MTSS1阳性表达者的中位总生存期为40.9个月,高于阴性表达者的21.5个月,差异有统计学意义(P<0.05)。Cox多因素分析显示MTSS1表达是影响NSCLC患者预后的独立因素。pcDNA3.1-MTSS1组的MTSS1蛋白水平高于pcDNA3.1组,且增殖比例和迁移率均低于pcDNA3.1组,差异均有统计学意义(P<0.05)。结论 MTSS1缺失表达在NSCLC的发生发展过程中发挥了重要作用,逆转MTSS1的表达有助于肺癌的防治。

乳腺癌原发灶和淋巴结转移灶中VEGF、nm23的表达变化及意义

目的：观察乳腺癌原发灶及淋巴结转移灶中血管内皮生长因子（VEGF）及转移抑制基因（m23）的表达变化及意义。方法选择2005年1～12月在我院行手术治疗且术前均未行抗癌治疗的60例乳腺癌患者，术后病理证实无同侧腋窝淋巴结转移24例（无转移组），伴有同侧腋窝淋巴结转移36例（转移组），采用免疫组化SP法检测乳腺癌原发灶和淋巴结转移灶中VEGF、nm23的表达，并分析VEGF与nm23的相关性。结果转移组原发灶中VEGF阳性表达率为91．7％，转移灶中为61．1％，无转移组VEGF阳性表达率为70．8％，转移组原发灶中VEGF阳性表达率明显高于转移灶及无转移组（P均＜0．05）。转移组nm23阳性表达率在原发灶中为16．7％，转移灶中为41．7％，无转移组nm23阳性表达率为45．8％，转移组原发灶中nm23阳性表达率明显低于转移灶及无转移组（P均＜0．05）。原发灶VEGF与nm23表达呈负相关（r＝-0．415，P＜0．05）。原发灶VEGF、nm23表达与淋巴结转移灶中VEGF、nm23表达无相关性。结论乳腺癌原发灶中VEGF表达明显高于、nm23表达明显低于淋巴结转移灶， VEGF、nm23与乳腺癌淋巴结转移密切相关，二者在乳腺癌发生和淋巴结转移中起拮抗作用。