粘蛋白MUC15对肝癌恶性生物学行为的调控作用及机制研究
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摘要
第一部分
粘蛋白MUC15对肝癌恶性生物学行为的调控作用及机制研究
研究背景和目的：
原发性肝细胞癌是全世界最常见的致命性恶性肿瘤之一，发病率在恶性肿瘤中位居第六位，而死亡率则占肿瘤相关死亡的第三位，更是肝硬化病人死亡的首要原因。分期较早的肿瘤病人，可通过肝切除术、肝移植和射频消融，得到有效的治疗。但大部分病人诊断时既为晚期，因为血管癌栓、子灶、包膜不全和多中心发生等情况的存在，缺乏有效的治疗，术后仍有很高的复发转移率，预后依然很差。因此，迫切需要探索新的治疗方法，鉴定新的肝癌进展分子标记，以建立新的更好的分子分型分层系统，并深刻理解肝癌术后转移复发的分子机制，这对于选择恰当的治疗方式，阻止肿瘤术后复发转移，延长患者生存十分重要。
粘蛋白是一类古老的高分子量糖蛋白家族，通常分为胞浆型及膜型，常被高度的O型糖基化包被。生理条件下，大部分上皮细胞中具有粘蛋白的表达。一般说来，粘蛋白的功能主要涉及水合、润滑和保护上皮表皮。肿瘤研究中，早期粘蛋白家族成员多以血清标记物的出现，为人们所熟知，如CA125（MUC16）,CA153（MUC1）等，这些成员多为分泌型粘蛋白。近年来，很多文献报道膜型粘蛋白在炎症向肿瘤的进展过程中，起到了很重要的作用。膜型粘蛋白为一类具有单次跨膜结构的粘蛋白家族成员，其N端位于胞外，可感受各种胞外信号如各种细胞因子、生长因子等的刺激，而C端位于胞浆内，涉及多条信号通路的活化。膜型粘蛋白家族成员包括MUC1, MUC3A, MUC3B,MUC4,MUC12, MUC13, MUC15, MUC16, MUC17和MUC20。
粘蛋白MUC15最初是从牛奶脂肪小泡的膜上被分离鉴定。在人类胎盘的发育过程中，MUC15的表达在胚胎晚期比胚胎早期要高，而且体外实验表明其表达水平与绒毛膜的侵袭能力呈负相关，过表达外源的MUC15，能够抑制滋养层样细胞JAR和JEG-3的侵袭能力。但是有趣的是，有文献报道在结肠腺癌的研究中，MUC15的表达异常升高的，并促进人类结肠癌细胞的恶性表型。那么，在肝癌发生发展及转移复发中，粘蛋白MUC15的表达情况如何，将发挥如何的作用，尚未见报道。
研究方法：
1.搜集临床肝癌标本，通过real-time RT-PCR、western blot、免疫组化技术检测MUC15在肝癌组织中转录水平、蛋白水平的表达情况；
2.完善肝癌样本的临床病理资料及随访预后信息，进行统计分析及预后分析，研究MUC15与临床病理特征的相关性及对肝癌总体生存及术后复发的预测价值；
3.利用慢病毒系统，建立MUC15过表达及干扰细胞系，采用CCK8、划痕实验、transwell迁移小室、Matrigel侵袭小室实验观察高低表达MUC15对肝癌细胞体外对增殖、迁移与侵袭能力的影响；
4.利用裸鼠皮下荷瘤及尾静脉注射肺转移膜型，研究高低表达MUC15对肝癌细胞体内对增殖、转移能力的影响；
5.利用real-time RT-PCR、Western blot技术，结合细胞因子刺激、抑制剂实验等方法，研究MUC15对MAPK及PI3K/Akt等信号通路的影响；
6.利用real-time RT-PCR、Western blot、免疫荧光、免疫共沉淀、流式细胞分析等技术，研究MUC15与EGFR的关系及对其功能的影响；
7.利用免疫组化方法，研究MUC15与p-Akt在肝癌样本中的相关性，并研究两者结合后，对肝癌预后判断的价值。
研究结果：
1.肝癌临床样本中MUC15在转录水平及蛋白水平均较癌旁组织降低；
2. MUC15低表达能够预测更具侵袭性的临床病理特征及肝癌病人更差的预后；
3.过表达MUC15能有效抑制肝细胞的迁移与侵袭能力；干扰MUC15则能促进肝癌细胞的迁移与侵袭能力；
4. MUC15通过阻断PI3K/Akt信号通路调节了MMP2、MMP7及TIMP2的表达；
5. MUC15与EGFR的相互作用促进了EGFR的入胞、泛素化降解，阻碍了其本身同源二聚体的形成，从而调节了PI3K/Akt信号通路的失活；
6. MUC15与p-Akt在临床样本中同样存在负相关关系，结合两者是强有力的肝癌预后预测因子；
7. DNA甲基化部分解释了HCC中MUC15mRNA水平的降低。
结论：
本研究工作发现，在肝细胞癌中粘蛋白MUC15在癌中较癌旁明显低表达，我们运用大样本HCC验证，发现这种低表达与肝癌的恶性临床病理指标存在明显的相关性，进一步的单因素及多因素分析显示MUC15是独立的术后预后风险因素。体内及体外的实验进一步证明过表达MUC15可以显著的抑制肝癌细胞的迁移及侵袭能力，并且这种抑制能力主要是通过抑制PI3K/Akt信号通路实现的。我们首次报道了MUC15和EGFR的相互作用，这种相互作用明显的减弱了EGF介导的EGFR的同源二聚化，并促进了EGFR在早期胞吞小泡中的重定位，及EGFR的泛素化降解，然后抑制了Akt介导的肝癌的进展和转移。
第二部分
CHKA在肝癌恶性进展中的作用与机制研究研究背景和目的：
肝癌为世界第六大常见恶性肿瘤，这些年，随着流行病学、影像学、分子生物学等学科的进步，对肝癌的认识从流行病、诊断、治疗、发病机理上来说，均有了长足的进步，但近年来肝癌相关的死亡率在全世界范围内仍呈现上升趋势。大部分肝癌患者诊断时已经是晚期，其总体生存率相比其他一些肿瘤仍然很低。因为晚期肿瘤术后的高复发转移率，绝大多数肝癌患者并非死于原发灶，而主要是死于肿瘤的复发与转移。因此深入研究导致肝癌发生发展与转移的分子机制对于完善目前的临床治疗方案有积极的意义。
胆碱激酶是脂类代谢中发挥重要作用的关键酶类。它是生物体细胞内催化胆碱为磷酸胆碱，最终合成生物膜磷脂双分子层的主要成分磷脂酰胆碱过程中的第一步关键酶。该酶由胆碱激酶α（CHKA）和胆碱激酶β（CHKB）两个基因编码，二者通过同二聚体或异二聚体方式形成有活性的胆碱激酶。近年来，很多研究显示胆碱激酶及其催化产物磷酸胆碱在多种肿瘤中呈高表达，包括乳腺癌、肺癌、结肠癌、膀胱癌、前列腺癌及卵巢癌，并且发现CHKA的表达水平与乳腺癌、肺癌和膀胱癌患者的临床预后存在相关性。一些研究小组还通过各种体内外实验证实CHKA具有癌基因的功能，这些结果均提示CHKA可能在恶性肿瘤的发生发展过程中发挥重要作用。然而，CHKA在肝癌中的表达情况如何，是否与临床预后相关以及是否参与肝癌的恶性进展过程，目前国内外尚未见有系统报道。
本研究旨在为深入理解CHKA在肝癌恶性进展过程中的作用提供实验依据，并为肝癌的治疗提供新的潜在靶点。研究方法：
1.通过real-time qPCR技术检测CHKA在肝癌组织的基因组水平和转录水平的拷贝数和表达丰度；
2.通过Western blot手段和免疫组化方法检测CHKA在肝癌组织中蛋白水平的表达情况；
3.通过运用质粒过表达技术以及siRNA介导的基因沉默技术调节CHKA的表达水平观察其对肝细胞增殖的影响；
4.通过划痕实验、transwell迁移小室、Matrigel侵袭小室实验观察高低表达CHKA对肝癌细胞迁移与侵袭能力的影响；
5.结合抑制剂实验和siRNA基因干扰实验，研究CHKA调控肝癌细胞恶性生物学行为的通路机制；
6.应用免疫组化方法结合临床病例资料和随访数据，分析判断CHKA的预后意义。
研究结果：
1.肝癌组织中CHKA基因拷贝数明显高于癌旁组织，并且在肝癌组织中CHKA蛋白呈普遍高表达；
2. CHKA并不明显影响肝癌细胞的增殖过程；
3.过表达CHKA可使肝细胞发生EMT转变；
4.过表达CHKA能促进肝细胞的迁移与侵袭能力；干扰CHKA则能有效抑制肝癌细胞的迁移与侵袭能力；
5.过表达CHKA激活PI3K/Akt信号通路；干扰CHKA则明显抑制PI3K/Akt通路；
6.抑制PI3K/Akt通路可明显减轻CHKA介导的促迁移与侵袭能力；
7.临床肝癌组织中CHKA的高表达与肿瘤微血管侵犯和肿瘤分期有关，并预示着患者更短的总体生存时间和更早的肿瘤复发。
结论：
本研究首先从临床肝癌患者癌组织样本入手，分析CHKA在肝癌中的表达情况。我们发现在肝癌基因组中CHKA拷贝数显著增加，其蛋白产物在肝癌中呈普遍高表达；随后通过过表达及干扰技术，研究CHKA对肝癌细胞生物学功能的影响；并进而阐明CHKA调控肝癌细胞生物学功能的具体通路机制。我们的数据显示CHKA主要是通过PI3K/Akt信号通路促进肝癌细胞发生侵袭与转移，提示PI3K/Akt通路在CHKA促进肝癌恶性进展过程中可能具有重要作用。本研究旨在为深入理解CHKA在肝癌恶性进展过程中的作用提供实验依据，并为肝癌的治疗提供新的潜在靶点。
PartⅠ:Studies on the roles and mechanisms ofMUC15in Hepatocarcinogenesis
Background&Aims: Mucins have been implicated in human carcinogenesis. Theaberrant expression of MUC15has been correlated with colorectal adenocarcinomasand may play a critical role in the negative regulation of trophoblast invasion inhuman placentas. However, the potential role of MUC15in HCC remains unknown.The authors therefore determined the expression profile, functions and underlyingmechanisms of MUC15in the pathogenesis of hepatocellular carcinoma.
Methods: MUC15expression levels were evaluated by immunohistochemistry,real-time RT-PCR and Western blotting assays. Clinical impact of MUC15wasassessed in a cohort of313HCC patients. Functional effect of MUC15was examinedby in vitro and in vivo assays.
Results: We demonstrated that expression of MUC15frequently decreases in HCC,which is significantly associated with tumor aggressive characteristics and poorprognosis. Functional studies showed that exogenous expression of MUC15ameliorates metastasis and local growth of HCC cells in vitro and in vivo, viadecreasing the transcription of MMP2, MMP7but upregulating TIMP2expressionwith a PI3K/Akt-depended manner. Importantly, the physical interaction of MUC15and EGFR resulting in EGFR relocation within early endosome is indispensible forMUC15-mediated PI3K/AKT signaling inactivation. Consistently, a significantinverse correlation between MUC15expression and p-Akt levels in clinical samplesindicated that combination of these two parameters shows incremental prognosticvalue.
Conclusions: MUC15is an independent prognostic biomarker and novel dimerizationpartner of EGFR, which involves in the negative regulation ofEGFR/PI3K/AKT-induced cell migration and invasion during the metastasis andprogression of HCC.
PartⅡ:CHKA Enhances Hepatocellular Carcinoma Progression andMetastasis via Phosphoinositol3-Kinase/AKT Pathway
Background&Aims: Choline kinase α (CHKA), the enzyme that converts choline tophosphocholine, has been implicated in human carcinogenesis. However, its potentialrole in HCC progression remains largely unexplored.
Methods: Overexpression and gene silencing experiments were performed to evaluatethe potential oncogenic role of CHKAin HCC.
Results: Here, we demonstrated that gene copy number of CHKA was elevated inhuman HCC genome and CHKAprotein was frequently overexpressed in HCC tissuesand cancer cell lines. Functional studies showed that ectopic expression of CHKAenhanced cell migration and invasion, whereas silencing CHKA expressioneffectively inhibited the migratory and invasive abilities of tumor cells. Further studyrevealed that Phosphoinositol3-Kinase (PI3K)/AKT pathway was mainly responsiblefor the oncogenic role of CHKA. Moreover, investigation of clinical HCC specimensshowed that increased expression of CHKA was closely correlated with advancedtumor stage and poor overall and disease-free survivals.
Conclusions: Our results suggest that CHKA promotes HCC progression andmetastasis mainly through PI3K/Akt pathway, which may provide new insights intothe pathogenesis of HCC. These findings indicate that CHKA might be a new targetfor treatment of liver cancer.
粘蛋白MUC15对肝癌恶性生物学行为的调控作用及机制研究
研究背景和目的：
原发性肝细胞癌是全世界最常见的致命性恶性肿瘤之一，发病率在恶性肿瘤中位居第六位，而死亡率则占肿瘤相关死亡的第三位，更是肝硬化病人死亡的首要原因。分期较早的肿瘤病人，可通过肝切除术、肝移植和射频消融，得到有效的治疗。但大部分病人诊断时既为晚期，因为血管癌栓、子灶、包膜不全和多中心发生等情况的存在，缺乏有效的治疗，术后仍有很高的复发转移率，预后依然很差。因此，迫切需要探索新的治疗方法，鉴定新的肝癌进展分子标记，以建立新的更好的分子分型分层系统，并深刻理解肝癌术后转移复发的分子机制，这对于选择恰当的治疗方式，阻止肿瘤术后复发转移，延长患者生存十分重要。
粘蛋白是一类古老的高分子量糖蛋白家族，通常分为胞浆型及膜型，常被高度的O型糖基化包被。生理条件下，大部分上皮细胞中具有粘蛋白的表达。一般说来，粘蛋白的功能主要涉及水合、润滑和保护上皮表皮。肿瘤研究中，早期粘蛋白家族成员多以血清标记物的出现，为人们所熟知，如CA125（MUC16）,CA153（MUC1）等，这些成员多为分泌型粘蛋白。近年来，很多文献报道膜型粘蛋白在炎症向肿瘤的进展过程中，起到了很重要的作用。膜型粘蛋白为一类具有单次跨膜结构的粘蛋白家族成员，其N端位于胞外，可感受各种胞外信号如各种细胞因子、生长因子等的刺激，而C端位于胞浆内，涉及多条信号通路的活化。膜型粘蛋白家族成员包括MUC1, MUC3A, MUC3B,MUC4,MUC12, MUC13, MUC15, MUC16, MUC17和MUC20。
粘蛋白MUC15最初是从牛奶脂肪小泡的膜上被分离鉴定。在人类胎盘的发育过程中，MUC15的表达在胚胎晚期比胚胎早期要高，而且体外实验表明其表达水平与绒毛膜的侵袭能力呈负相关，过表达外源的MUC15，能够抑制滋养层样细胞JAR和JEG-3的侵袭能力。但是有趣的是，有文献报道在结肠腺癌的研究中，MUC15的表达异常升高的，并促进人类结肠癌细胞的恶性表型。那么，在肝癌发生发展及转移复发中，粘蛋白MUC15的表达情况如何，将发挥如何的作用，尚未见报道。
研究方法：
1.搜集临床肝癌标本，通过real-time RT-PCR、western blot、免疫组化技术检测MUC15在肝癌组织中转录水平、蛋白水平的表达情况；
2.完善肝癌样本的临床病理资料及随访预后信息，进行统计分析及预后分析，研究MUC15与临床病理特征的相关性及对肝癌总体生存及术后复发的预测价值；
3.利用慢病毒系统，建立MUC15过表达及干扰细胞系，采用CCK8、划痕实验、transwell迁移小室、Matrigel侵袭小室实验观察高低表达MUC15对肝癌细胞体外对增殖、迁移与侵袭能力的影响；
4.利用裸鼠皮下荷瘤及尾静脉注射肺转移膜型，研究高低表达MUC15对肝癌细胞体内对增殖、转移能力的影响；
5.利用real-time RT-PCR、Western blot技术，结合细胞因子刺激、抑制剂实验等方法，研究MUC15对MAPK及PI3K/Akt等信号通路的影响；
6.利用real-time RT-PCR、Western blot、免疫荧光、免疫共沉淀、流式细胞分析等技术，研究MUC15与EGFR的关系及对其功能的影响；
7.利用免疫组化方法，研究MUC15与p-Akt在肝癌样本中的相关性，并研究两者结合后，对肝癌预后判断的价值。
研究结果：
1.肝癌临床样本中MUC15在转录水平及蛋白水平均较癌旁组织降低；
2. MUC15低表达能够预测更具侵袭性的临床病理特征及肝癌病人更差的预后；
3.过表达MUC15能有效抑制肝细胞的迁移与侵袭能力；干扰MUC15则能促进肝癌细胞的迁移与侵袭能力；
4. MUC15通过阻断PI3K/Akt信号通路调节了MMP2、MMP7及TIMP2的表达；
5. MUC15与EGFR的相互作用促进了EGFR的入胞、泛素化降解，阻碍了其本身同源二聚体的形成，从而调节了PI3K/Akt信号通路的失活；
6. MUC15与p-Akt在临床样本中同样存在负相关关系，结合两者是强有力的肝癌预后预测因子；
7. DNA甲基化部分解释了HCC中MUC15mRNA水平的降低。
结论：
本研究工作发现，在肝细胞癌中粘蛋白MUC15在癌中较癌旁明显低表达，我们运用大样本HCC验证，发现这种低表达与肝癌的恶性临床病理指标存在明显的相关性，进一步的单因素及多因素分析显示MUC15是独立的术后预后风险因素。体内及体外的实验进一步证明过表达MUC15可以显著的抑制肝癌细胞的迁移及侵袭能力，并且这种抑制能力主要是通过抑制PI3K/Akt信号通路实现的。我们首次报道了MUC15和EGFR的相互作用，这种相互作用明显的减弱了EGF介导的EGFR的同源二聚化，并促进了EGFR在早期胞吞小泡中的重定位，及EGFR的泛素化降解，然后抑制了Akt介导的肝癌的进展和转移。
第二部分
CHKA在肝癌恶性进展中的作用与机制研究研究背景和目的：
肝癌为世界第六大常见恶性肿瘤，这些年，随着流行病学、影像学、分子生物学等学科的进步，对肝癌的认识从流行病、诊断、治疗、发病机理上来说，均有了长足的进步，但近年来肝癌相关的死亡率在全世界范围内仍呈现上升趋势。大部分肝癌患者诊断时已经是晚期，其总体生存率相比其他一些肿瘤仍然很低。因为晚期肿瘤术后的高复发转移率，绝大多数肝癌患者并非死于原发灶，而主要是死于肿瘤的复发与转移。因此深入研究导致肝癌发生发展与转移的分子机制对于完善目前的临床治疗方案有积极的意义。
胆碱激酶是脂类代谢中发挥重要作用的关键酶类。它是生物体细胞内催化胆碱为磷酸胆碱，最终合成生物膜磷脂双分子层的主要成分磷脂酰胆碱过程中的第一步关键酶。该酶由胆碱激酶α（CHKA）和胆碱激酶β（CHKB）两个基因编码，二者通过同二聚体或异二聚体方式形成有活性的胆碱激酶。近年来，很多研究显示胆碱激酶及其催化产物磷酸胆碱在多种肿瘤中呈高表达，包括乳腺癌、肺癌、结肠癌、膀胱癌、前列腺癌及卵巢癌，并且发现CHKA的表达水平与乳腺癌、肺癌和膀胱癌患者的临床预后存在相关性。一些研究小组还通过各种体内外实验证实CHKA具有癌基因的功能，这些结果均提示CHKA可能在恶性肿瘤的发生发展过程中发挥重要作用。然而，CHKA在肝癌中的表达情况如何，是否与临床预后相关以及是否参与肝癌的恶性进展过程，目前国内外尚未见有系统报道。
本研究旨在为深入理解CHKA在肝癌恶性进展过程中的作用提供实验依据，并为肝癌的治疗提供新的潜在靶点。研究方法：
1.通过real-time qPCR技术检测CHKA在肝癌组织的基因组水平和转录水平的拷贝数和表达丰度；
2.通过Western blot手段和免疫组化方法检测CHKA在肝癌组织中蛋白水平的表达情况；
3.通过运用质粒过表达技术以及siRNA介导的基因沉默技术调节CHKA的表达水平观察其对肝细胞增殖的影响；
4.通过划痕实验、transwell迁移小室、Matrigel侵袭小室实验观察高低表达CHKA对肝癌细胞迁移与侵袭能力的影响；
5.结合抑制剂实验和siRNA基因干扰实验，研究CHKA调控肝癌细胞恶性生物学行为的通路机制；
6.应用免疫组化方法结合临床病例资料和随访数据，分析判断CHKA的预后意义。
研究结果：
1.肝癌组织中CHKA基因拷贝数明显高于癌旁组织，并且在肝癌组织中CHKA蛋白呈普遍高表达；
2. CHKA并不明显影响肝癌细胞的增殖过程；
3.过表达CHKA可使肝细胞发生EMT转变；
4.过表达CHKA能促进肝细胞的迁移与侵袭能力；干扰CHKA则能有效抑制肝癌细胞的迁移与侵袭能力；
5.过表达CHKA激活PI3K/Akt信号通路；干扰CHKA则明显抑制PI3K/Akt通路；
6.抑制PI3K/Akt通路可明显减轻CHKA介导的促迁移与侵袭能力；
7.临床肝癌组织中CHKA的高表达与肿瘤微血管侵犯和肿瘤分期有关，并预示着患者更短的总体生存时间和更早的肿瘤复发。
结论：
本研究首先从临床肝癌患者癌组织样本入手，分析CHKA在肝癌中的表达情况。我们发现在肝癌基因组中CHKA拷贝数显著增加，其蛋白产物在肝癌中呈普遍高表达；随后通过过表达及干扰技术，研究CHKA对肝癌细胞生物学功能的影响；并进而阐明CHKA调控肝癌细胞生物学功能的具体通路机制。我们的数据显示CHKA主要是通过PI3K/Akt信号通路促进肝癌细胞发生侵袭与转移，提示PI3K/Akt通路在CHKA促进肝癌恶性进展过程中可能具有重要作用。本研究旨在为深入理解CHKA在肝癌恶性进展过程中的作用提供实验依据，并为肝癌的治疗提供新的潜在靶点。
PartⅠ:Studies on the roles and mechanisms ofMUC15in Hepatocarcinogenesis
Background&Aims: Mucins have been implicated in human carcinogenesis. Theaberrant expression of MUC15has been correlated with colorectal adenocarcinomasand may play a critical role in the negative regulation of trophoblast invasion inhuman placentas. However, the potential role of MUC15in HCC remains unknown.The authors therefore determined the expression profile, functions and underlyingmechanisms of MUC15in the pathogenesis of hepatocellular carcinoma.
Methods: MUC15expression levels were evaluated by immunohistochemistry,real-time RT-PCR and Western blotting assays. Clinical impact of MUC15wasassessed in a cohort of313HCC patients. Functional effect of MUC15was examinedby in vitro and in vivo assays.
Results: We demonstrated that expression of MUC15frequently decreases in HCC,which is significantly associated with tumor aggressive characteristics and poorprognosis. Functional studies showed that exogenous expression of MUC15ameliorates metastasis and local growth of HCC cells in vitro and in vivo, viadecreasing the transcription of MMP2, MMP7but upregulating TIMP2expressionwith a PI3K/Akt-depended manner. Importantly, the physical interaction of MUC15and EGFR resulting in EGFR relocation within early endosome is indispensible forMUC15-mediated PI3K/AKT signaling inactivation. Consistently, a significantinverse correlation between MUC15expression and p-Akt levels in clinical samplesindicated that combination of these two parameters shows incremental prognosticvalue.
Conclusions: MUC15is an independent prognostic biomarker and novel dimerizationpartner of EGFR, which involves in the negative regulation ofEGFR/PI3K/AKT-induced cell migration and invasion during the metastasis andprogression of HCC.
PartⅡ:CHKA Enhances Hepatocellular Carcinoma Progression andMetastasis via Phosphoinositol3-Kinase/AKT Pathway
Background&Aims: Choline kinase α (CHKA), the enzyme that converts choline tophosphocholine, has been implicated in human carcinogenesis. However, its potentialrole in HCC progression remains largely unexplored.
Methods: Overexpression and gene silencing experiments were performed to evaluatethe potential oncogenic role of CHKAin HCC.
Results: Here, we demonstrated that gene copy number of CHKA was elevated inhuman HCC genome and CHKAprotein was frequently overexpressed in HCC tissuesand cancer cell lines. Functional studies showed that ectopic expression of CHKAenhanced cell migration and invasion, whereas silencing CHKA expressioneffectively inhibited the migratory and invasive abilities of tumor cells. Further studyrevealed that Phosphoinositol3-Kinase (PI3K)/AKT pathway was mainly responsiblefor the oncogenic role of CHKA. Moreover, investigation of clinical HCC specimensshowed that increased expression of CHKA was closely correlated with advancedtumor stage and poor overall and disease-free survivals.
Conclusions: Our results suggest that CHKA promotes HCC progression andmetastasis mainly through PI3K/Akt pathway, which may provide new insights intothe pathogenesis of HCC. These findings indicate that CHKA might be a new targetfor treatment of liver cancer.
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