• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Development of Epstein-Barr virus-associated gastric cancer: Infection, inflammation, and oncogenesis

    2022-12-01 01:45:42HisashilizasaAndyVisiKartikaSintayehuFekaduShunpeiOkadaDaichiOnomuraAfifahFatimahAzzahraAhmadWadiMosammatMahmudaKhatunThinMyatMoeJunNishikawaHironoriYoshiyama
    World Journal of Gastroenterology 2022年44期

    Hisashi lizasa,Andy Visi Kartika, Sintayehu Fekadu, Shunpei Okada, Daichi Onomura, Afifah FatimahAzzahra Ahmad Wadi, Mosammat Mahmuda Khatun, Thin Myat Moe, Jun Nishikawa, Hironori Yoshiyama

    Abstract Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) cells originate from a single-cell clone infected with EBV. However, more than 95% of patients with gastric cancer have a history of Helicobacter pylori (H. pylori) infection, and H. pylori is a major causative agent of gastric cancer. Therefore, it has long been argued that H. pylori infection may affect the development of EBVaGC, a subtype of gastric cancer. Atrophic gastrointestinal inflammation, a symptom of H. pylori infection,is observed in the gastric mucosa of EBVaGC. Therefore, it remains unclear whether H. pylori infection is a cofactor for gastric carcinogenesis caused by EBV infection or whether H. pylori and EBV infections act independently on gastric cancer formation. It has been reported that EBV infection assists in the oncogenesis of gastric cancer caused by H. pylori infection. In contrast, several studies have reported that H. pylori infection accelerates tumorigenesis initiated by EBV infection. By reviewing both clinical epidemiological and experimental data, we reorganized the role of H. pylori and EBV infections in gastric cancer formation.

    Key Words: Helicobacter pylori; Epstein-Barr virus; Epstein-Barr virus-associated gastric cancer; Coreceptor; Inflammation; Oncogenesis

    INTRODUCTION

    Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) accounts for 10% of all gastric cancers. At the same time, more than 95% of patients with gastric cancer have a history ofHelicobacter pylori(H.pylori) infection. Thus, the question arises as to whetherH. pyloriand EBV infections promote gastric cancer formation in a dependent or independent manner. The high prevalence of gastric cancer in Asia,South America, and the Middle East is also intriguing.

    EBV IS AN ONCOGENIC HUMAN HERPESVIRUS

    EBV infects B lymphocytes and epithelial cells and is an oncogenic virus that assists in the proliferation of latently infected cells, resulting in the development of Burkitt lymphoma, Hodgkin lymphoma,nasopharyngeal carcinoma, and EBVaGC[1].

    More than 90% of adults are latently infected with EBV; however, cytotoxic T lymphocytes that recognize EBV antigens suppress the proliferation of viral antigen-positive cells. When the local or systemic immune function is compromised, EBV-positive cells begin to proliferate. B lymphocytes that migrate to local areas where immune surveillance is weak often transition to lytic infection, resulting in viral production. Under such conditions, EBV appears to be transmitted to and infects gastric epithelial cells. The expression of EBV genes causes epithelial cells to acquire proliferative properties and resist apoptosis, and cells that escape immunological elimination may begin proliferating[2].

    EBV-ASSOCIATED GASTRIC CANCER

    Molecular features

    Classification of gastric cancer by molecular mechanism was performed through an exhaustive analysis of next-generation sequencing data from numerous cases. The results divided gastric cancer into the following four molecular subtypes: Microsatellite instability (MSI), chromosomal instability (CIN),genomically stable (GS), and EBV[3]. These classifications have facilitated the identification of specific therapeutic candidates for each subtype of gastric cancer, and have revealed that each of these four subtypes is driven by a specific developmental mechanism that needs to be clarified individually. In particular, the molecular biology of EBVaGC is characterized by frequent and extensive methylation of the promoter regions of tumor cell genes[4].De novoEBV infection induces DNA methylation in more than 3000 gene promoter regions within 4 wk[4]. However, methylation of the promoter of the mismatch repair geneMLH1, which is frequently observed in MSI, is not observed in EBVaGC[5]. In addition to inactivation by DNA methylation, the EBV genome binds to heterochromatin, a region of inactivation that causes aberrant activation of the region (enhancer infestation) and increases the expression of surrounding proto-oncogenes[6].

    Clinical features

    In EBVaGC, which accounts for 5%-10% of all gastric cancers, all tumor cells are infected with EBV.Endoscopy is the most informative method for diagnosing gastric cancer. EBVaGC is observed as a superficial depressed lesion in the upper part of the stomach. Using endoscopic biopsy specimens, EBVencoded RNAin situhybridization (EBER-ISH), stains all gastric cancer cells positive for EBER, even in the intramucosal cancer stage[7]. The histological hallmark of EBVaGC is lymphoepithelioma-like carcinoma, in which a diffuse lymphocytic infiltrate is observed around EBER-positive epithelial tumor cells[8]. Furthermore, EBVaGC tumor cells are derived from the proliferation of a single EBV-infected epithelial cell[8,9].

    Many studies have shown a male predominance (2-fold) of EBVaGC, suggesting that the risk may exist in male lifestyle and occupational factors[10]. The percentage of patients with EBVaGC to those with total gastric cancer is higher in younger patients. In men, the proportion of EBVaGC decreases with increasing age, especially in patients with pyloric gastric cancer. In women, the decrease in the proportion of EBVaGC with increasing age is unclear. Consumption of salty foods that cause mechanical damage to the gastric epithelium as well as exposure to wood and iron filings are associated with a higher EBVaGC risk[11].

    EBVaGC is a gastric cancer with a relatively good prognosis. A Dutch study reported that EBVaGC is characterized by fewer lymph node metastases, less residual disease, and younger patient age, which results in longer disease-free survival[12]. Cohort study data from TCGA also reported that EBVaGC has the best recurrence-free period and overall survival compared to MSI, GS, and CIN subtypes[13].

    EBVaGC tumors are frequently found in non-antral parts of the stomach[10,14]. In contrast,H. pyloriassociated gastric cancer mostly occurs in the antral region[10]. Because moderate to severe atrophic gastric mucosa due toH. pyloriinfection was characteristically observed surrounding early gastric cancers, gastritis may play an important role in the tumorigenesis of EBVaGC[14]. Development of gastric cancer is supposed to follow the "infection, inflammation, and carcinogenesis" route, which consists ofH. pyloriinfection followed by chronic gastritis, intestinal metaplasia, and cancer. In contrast,in the case of EBVaGC, it is controversial whether tumor formation is initiated by EBV-infected normal mucosal cells or promoted by EBV-infected cells in precancerous lesions[15]. Abeet al[16] performed EBER-ISH on 1110 sections of non-neoplastic gastric mucosal tissue from 300 cases and found 2 (0.18%)ductal-level EBER-positive lesions.

    The mutual contribution of EBV andH. pyloriin the carcinogenesis will be discussed later in the chapter “Inflammation and carcinogenesis”.

    EBV INFECTION OF EPITHELIAL CELLS

    EBV infects B lymphocytes through the binding of the viral glycoprotein gp350 to the high-affinity receptor CD21, followed by binding of gp42 to HLA class II molecules, resulting in membrane fusion[17]. In contrast, when low-affinity co-receptors are used to infect CD21-negative epithelial cells, the infection efficiency is extremely low (Figure 1).

    The CD21-independent routes of epithelial cell infection include the following: (1) The viral envelope glycoprotein gp350/220 binds to CD35; (2) Integrins αVβ5, αVβ6, and αVβ8 interact with the viral envelope glycoprotein gH/gL complex to fuse the viral envelope with the epithelial cell membrane; (3)The BMRF2 membrane protein expressed during EBV lytic infection binds to α3, α5, αV, and β1 integrins; and (4) EphA2 and NMHC-IIA bind to gH/gL produced by many herpesviruses and enhance infection efficiency.

    A previous study reported that a boy with X-linked agammaglobulinemia who did not have mature B lymphocytes due to a genetic enzymatic deficiency did not develop an EBV infection[18]. EBV infection of epithelial cells was considered to occur after EBV infection of B lymphocytes because the epithelial cells of the affected boy were intact. EBV-infected B lymphocytes are believed to carry and deliver EBV to the epithelial cellsviacell-to-cell transfer. In the case of CD21-independent infection, the efficiency of epithelial cell infection by cell-to-cell transfer is more than 1000 times higher than that of direct epithelial cell infection by EBV particles[19]. It is speculated that infection of epithelial cellsviaB lymphocytes is promoted when viral activation and lymphocyte infiltration are accompanied by inflammation(Figure 1).

    EBV-associated gastric cancer-derived cell lines

    In EBVaGC, all tumor cells are infected with EBV. However, cell lines established from gastric cancer tissues, similar to those in nasopharyngeal carcinoma, are almost entirely EBV-negative[20]. The EBV genome in EBVaGC tumor cells exists as a plasmid-like episome that does not integrate into the host chromosomes. However, the presence of the virus does not appear to favor cell growthin vitro. Rather,it may be more convenient forin vitrocell growth to avoid the use of extra energy to maintain the episomes. Alternatively, the expression of viral genes such as microRNAs may be crucial for tumor cells to evade elimination by thein vivoimmune system. In fact, EBV-positive KT cells established from EBVaGC can only be passaged by transplantation into SCID mice and cannot be expanded in anin vitroculture system[21]. SNU-719, YCCEL1, and NCC-24 are rare cells established from EBVaGC and can be propagatedin vitro. These cell lines appear to be unique because the presence of EBV episomes is essential for their growth. Experiments with hydroxyurea and EBNA1 siRNAs were not successful in shedding the EBV episome from SNU-719 cells[22].

    Gastric epithelial cell lines infected with recombinant EBV

    We established gastric epithelial cells infected with recombinant EBV, where a drug-resistant gene was inserted into the nonessentialBXLF1(thymidine kinase) gene (Figure 2). It is possible to elucidate the oncogenic molecular mechanism of EBV-infected epithelial cells by comparing EBV-positive cells with EBV-negative cells. EBV infection markedly promotes the proliferation of gastric epithelial cells[23].

    EBV-infected gastric epithelial cells also exhibit type I latent infection that expresses EBNA1 and LMP2A, similar to that in EBVaGCin vivo. EBNA1 promotes tumorigenesisviap53 ubiquitination,suppresses transforming growth factor-β signaling, and enhances the transcription of the anti-apoptotic protein survivin[24]. In contrast, LMP2A activates PI3K/Akt signaling similar to that activated by B-cell receptor stimulation, increases survivin expression, and resists apoptosis[25]. LMP2A also induces DNA methyltransferases, resulting in epigenetic changes in infected cells[26].BARF1is strongly expressed as a latent gene in EBV-associated epithelial tumors[27]. Nasopharyngeal carcinoma-derived cells infected with recombinant EBV constitutively expressingBARF1exhibit resistance to apoptosis[28].

    In addition to the oncogenic activity of EBV proteins expressed in type I latent infections, non-coding RNAs (miRNAs and EBERs) that are not translated into proteins have been investigated. Multiple BART miRNAs cooperatively repress lytic replication[29]. BART miRNAs also downregulate pro- and antiapoptotic mediators such as caspase 3[30]. EBERs bind to protein kinase R and disrupt innate immune function[31]. Elimination of EBER2 from the EBV genome reduces the efficiency of B lymphocyte transformation[32].

    INFLAMMATION AND CARCINOGENESIS

    Clinical observation

    It is very difficult to collect EBVaGC cases withoutH. pyloriinfection, because most patients with gastric cancer are infected withH. pylori[33,34]. However, a clinical study was conducted to investigate the relationship between EBV infection,H. pyloriinfection, and atrophic gastritis in 468 patients with chronic gastritis[35]. This study confirmed that patients who were EBV-positive had a lower pepsinogen I/pepsinogen II ratio than patients who were EBV-negative. EBV infection significantly increases the risk of atrophic gastritis, especially inH. pylori-negative patients. However, a report from Mexico mentioned that EBER1in situhybridization showed that EBV infection of epithelial cells could be detected in gastric cancers as well as in one-third of non-atrophic gastritis samples[36]. This study showed that EBV infection affected early cancer precursor lesions. However, it is difficult to determine whether EBV causes cancer directly or indirectly by triggering inflammation.

    Inflammation and initiation of innate immune mechanisms promote EBV activation, although it is difficult to assess the extent to which these mechanisms are involved in tumorigenesis of EBV-infected cells (Figure 3). EBV proliferation occurs at the early stage of EBVaGC formation because early antigensimmunoglobulin G (IgG) and viral capsid antigen-IgG antibodies against early viral antigens and capsids are elevated in the sera of patients with EBVaGC. In addition, while the incidence of EBVaGC is approximately 10% worldwide, the incidence of gastric cancer after surgical invasion by gastric anastomosis increases by three times (30%)[8].

    Here, we investigated the relationship betweenH. pylori-associated gastritis and EBV propagation in the stomach. Gastric biopsy specimens were collected from patients with chronic atrophic gastritis and categorized into three histopathological stages: Mild, moderate, and severe. The specimens were subjected to DNA extraction and quantitative polymerase chain reaction to quantify EBV genome copy numbers[37]. More than 900 copies of the EBV genome have been frequently detected in patients with moderate atrophic gastritis. In other words, EBV frequently activates proliferation in patients withH.pyloriinfection with moderate chronic atrophic gastritis and strong histological inflammation.

    In contrast, EBVaGC is significantly associated with marked mucosal atrophy and moderate to marked lymphocytic infiltration, but there is no direct association with intestinal metaplasia[7].Although this appears to indicate that EBVaGC is not directly associated withH. pyloriinfection, this result is consistent with our findings. This is because the intestinal metaplastic epithelium resulting from prolonged gastritis is an unsuitable mucosal environment for the growth of bothH. pyloriand EBV[38].

    Experimental observation

    Several studies have been investigated the interaction between EBV andH. pyloriin gastric epithelial cell lines. Because it is difficult to infect the epithelial cells with the two microorganisms simultaneously,experiments have been conducted on sequential infection with EBV first andH. pylorisecond, or vice versa.

    Persistent infection of the gastric mucosa by CagA-positiveH. pyloristrains causes gastric cancer. This is because the tyrosine-phosphorylated CagA protein binds to the tyrosine phosphatase SHP2 in gastric epithelial cells, activatingRasoncogene. In contrast, SHP1, which competes with SHP2 weakens the oncogenic activity of SHP2. Sajuet al[39] showed that EBV infection of gastric epithelial cells activates host cell promoter methylation and decreases SHP1 expression[39]. In other words, SHP2 activity is relatively higher and EBV infection promotes carcinogenesis ofH. pyloriassociated gastric carcinoma.The induction of DNA methylase by EBV infection in gastric epithelial cells also decreases the expression of tumor suppressor genes such asAPC,breast cancer susceptibility gene 1, andphosphatase and tensin homolog deleted from chromosome 10(PTEN)[40].

    Furthermore, activation of innate immune signals byH. pyloriattachment enhances the expression of the EBV co-receptor EPHA2 in gastric epithelial cells, thereby increasing the frequency of EBV infection in epithelial cells[41]. Another study demonstrated that organoids derived from gastric cancer cells were infected with EBV but did not infect those derived from the normal gastric epithelium[42]. The probable reason for this is that gastric organoids maintain cell polarity and express EPHA2 only between cells.Therefore, the localization of EPHA2 might change due to gastric epithelial cell injury caused byH.pyloriinfection or by a prior gene mutation, which subsequently facilitates EBV infection.

    TUMORIGENIC MECHANISM OF EBV-INFECTED EPITHELIAL CELLS

    At present, it is difficult to infect primary gastric epithelial cells with EBV and immortalize them.Instead, gastric epithelial cell lines persistently infected with EBV have been used to elucidate the tumorigenic mechanisms of EBV genes during latent infections.

    EBV genes that encode untranslational RNA

    The EBV genome contains two miRNA clusters, consisting of four BHRF1 miRNAs and 40 BART miRNAs. Although BHRF1 miRNA is poorly expressed in epithelial cells, BART miRNAs are highly expressed in latently infected epithelial cells and play a substantial role in tumorigenesis[43].

    Epigenetic changes of gene expression in EBV-infected epithelial cells

    Modification of gene expressionviamethylation is frequently observed in patients with EBVaGC.Tumor suppressor genes, such asp14,p16,p73,PTEN,APC,RASSF1A, andCXXC4, are repressed by promoter methylation. And the expression of molecules important for cell invasion, including THBS1,E-cadherin (CDH1), and TIMP2, is also repressed by promoter methylation. The decreased expression of these molecules may be involved in carcinogenic processes[44].

    Multiple EBV episomal DNAs have been shown to approach enhancer sites in the genome, alter the surrounding chromatin structure (enhancer infestation), and activate genes such as transcription factors[6]. Although epigenetic analyses have been conducted to understand tumorigenesis, the overall mechanism remains unclear.

    Model of tumorigenesis for epithelial EBV infection

    Viral gene products transcribed in cells latently infected with EBV confer resistance to apoptosis.EBVgene products also accumulate mutations in the genes of the infected cells. Genetic changes in infected cells further affectEBVgene expression and alter intercellular communication, including the cross-talk between EBV-infected epithelial cells and immune cells[45] or epithelial-mesenchymal transition[46]. In other words, changes induced by persistent EBV infection in host cell signaling and host immune responses advance the tumorigenic stage[47].

    FUTURE PROSPECTS

    With the progress in research on EBER, miRNA, and long non-coding RNA, the functions of these molecules in latent EBV-infected cells are being elucidated. A highly tumorigenic B81 EBV strain was isolated from a patient with nasopharyngeal carcinoma[48]; however, an EBV strain unique to gastric cancer has not yet been isolated.

    Host gene mutations frequently observed in EBVaGC, including changes inPIK3CA,ARID1A,PD-L1,andPD-L2[3] are considered to affect histological characteristics, clinical course, and response to treatment. EBV-induced tumorigenesis is believed to be affected by environmental factors such as previous infections; however, the molecular basis that characterizes EBVaGC remains to be elucidated.

    Considering that EBVaGC most strongly expressesPD-L1andPD-L2among the four molecular subtypes of gastric cancer, immune checkpoint inhibitors are expected to be effective therapeutic agents for EBVaGC[49,50].PIK3CAmutations andJAK2amplification are frequently observed in EBVaGC.Therefore, PI3K and JAK2 inhibitors may be effective. Other EBNA-1 inhibitors are also expected to be EBV-specific therapeutic agents[51].

    CONCLUSION

    Several clinical and experimental data support the etiological role ofH. pyloriin EBV-associated gastric cancer.

    FOOTNOTES

    Author contributions:Iizasa H and Okada S contributed to the manuscript writing; Kartika AV, Fekadu S, and Wadi AFAA contributed to the graphic writing; Onomura D, Khatun MM and Moe TM contributed to literature search;Nishikawa J contributed to the study idea and study design; Yoshiyama H contributed to the study idea, study design, manuscript writing, and the final revision of the manuscript.

    Supported byGrant-in-Aid for Scientific Research From the Ministry of Education, Culture, Science and Technology of Japan, No. 21K07054 (Hironori Yoshiyama) and No. 22K07101 (Hisashi Iizasa).

    Conflict-of-interest statement:All the authors report no relevant conflicts of interest for this article.

    Open-Access:This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

    Country/Territory of origin:Japan

    ORCID number:Jun Nishikawa 0000-0002-6695-9754; Hironori Yoshiyama 0000-0001-7588-278X.

    Corresponding Author's Membership in Professional Societies:Japanese Cancer Association, No. 19950.

    S-Editor:Fan JR

    L-Editor:A

    P-Editor:Fan JR

    我的女老师完整版在线观看| 欧美 亚洲 国产 日韩一| 久久精品久久久久久久性| 欧美97在线视频| 亚洲久久久国产精品| 日本免费在线观看一区| 国产精品一国产av| 9色porny在线观看| 99热6这里只有精品| 日韩视频在线欧美| 永久网站在线| 国产成人精品婷婷| 免费观看的影片在线观看| 欧美 日韩 精品 国产| 赤兔流量卡办理| 亚洲成色77777| 亚洲精品日韩在线中文字幕| 精品一区在线观看国产| 日本欧美国产在线视频| 国产日韩欧美在线精品| 国产成人精品久久久久久| 久久午夜福利片| 超碰97精品在线观看| 久久毛片免费看一区二区三区| 午夜福利在线观看免费完整高清在| 久久久久精品久久久久真实原创| 国产成人免费无遮挡视频| 另类精品久久| 91精品三级在线观看| 亚洲激情五月婷婷啪啪| 9色porny在线观看| 亚洲精品成人av观看孕妇| 欧美97在线视频| 中文字幕人妻丝袜制服| 各种免费的搞黄视频| 男男h啪啪无遮挡| 婷婷色av中文字幕| 亚洲国产日韩一区二区| 成人国产麻豆网| 人人澡人人妻人| 男人爽女人下面视频在线观看| 又黄又爽又刺激的免费视频.| 国产成人精品在线电影| www.色视频.com| 美女福利国产在线| 日日啪夜夜爽| 夜夜看夜夜爽夜夜摸| 一区二区av电影网| 精品久久久精品久久久| 国产亚洲精品第一综合不卡 | 伊人亚洲综合成人网| 国产精品国产三级国产av玫瑰| 久久午夜福利片| 亚洲精品乱码久久久v下载方式| 不卡视频在线观看欧美| 汤姆久久久久久久影院中文字幕| 青青草视频在线视频观看| 九色亚洲精品在线播放| 少妇被粗大的猛进出69影院 | 国产黄频视频在线观看| 欧美少妇被猛烈插入视频| 中文乱码字字幕精品一区二区三区| 涩涩av久久男人的天堂| 大陆偷拍与自拍| 草草在线视频免费看| 少妇猛男粗大的猛烈进出视频| 婷婷色av中文字幕| 国产一区二区三区综合在线观看 | 18禁在线播放成人免费| 国产视频内射| 国产精品99久久久久久久久| 精品久久久久久久久亚洲| 在线观看美女被高潮喷水网站| 麻豆乱淫一区二区| 国产欧美亚洲国产| 日本wwww免费看| 91精品伊人久久大香线蕉| 久久久久久久大尺度免费视频| 精品人妻熟女毛片av久久网站| 国产午夜精品久久久久久一区二区三区| 中国国产av一级| 久久人人爽人人片av| 国产av一区二区精品久久| 人成视频在线观看免费观看| 久久ye,这里只有精品| 国产黄色视频一区二区在线观看| 国产精品不卡视频一区二区| 国产 一区精品| 校园人妻丝袜中文字幕| 三上悠亚av全集在线观看| 少妇高潮的动态图| 久久久久久久久大av| 王馨瑶露胸无遮挡在线观看| 久久久久久久亚洲中文字幕| 交换朋友夫妻互换小说| 夫妻午夜视频| 国产亚洲一区二区精品| 欧美激情极品国产一区二区三区 | 91在线精品国自产拍蜜月| 飞空精品影院首页| 波野结衣二区三区在线| 五月玫瑰六月丁香| 少妇人妻精品综合一区二区| 国产精品99久久久久久久久| 亚洲欧洲国产日韩| 国产精品久久久久成人av| 亚洲av成人精品一区久久| 欧美三级亚洲精品| 黑人猛操日本美女一级片| 国产 精品1| 欧美变态另类bdsm刘玥| 婷婷色麻豆天堂久久| 国产亚洲最大av| 在线免费观看不下载黄p国产| 国产精品人妻久久久久久| 国产黄色免费在线视频| 啦啦啦中文免费视频观看日本| 欧美日韩亚洲高清精品| 色94色欧美一区二区| 美女国产视频在线观看| 国产精品久久久久久精品电影小说| 久久精品熟女亚洲av麻豆精品| 成人毛片60女人毛片免费| 欧美国产精品一级二级三级| 欧美丝袜亚洲另类| 国产在线免费精品| 一本色道久久久久久精品综合| av不卡在线播放| 秋霞伦理黄片| av免费观看日本| 国产高清有码在线观看视频| 91成人精品电影| 国产成人精品久久久久久| 午夜久久久在线观看| 国产精品久久久久成人av| av线在线观看网站| 午夜免费观看性视频| 80岁老熟妇乱子伦牲交| 精品一品国产午夜福利视频| 91成人精品电影| 国产精品麻豆人妻色哟哟久久| 日韩电影二区| 91精品三级在线观看| 99视频精品全部免费 在线| 桃花免费在线播放| 欧美精品亚洲一区二区| 国产一区二区三区综合在线观看 | 日日爽夜夜爽网站| 大片电影免费在线观看免费| 韩国av在线不卡| 欧美+日韩+精品| 欧美bdsm另类| 男人爽女人下面视频在线观看| 国产精品国产av在线观看| 国产精品成人在线| 嫩草影院入口| 国产淫语在线视频| 一区在线观看完整版| 91精品伊人久久大香线蕉| 精品亚洲成国产av| 这个男人来自地球电影免费观看 | av有码第一页| 一级a做视频免费观看| 秋霞在线观看毛片| 亚洲成色77777| 中文精品一卡2卡3卡4更新| 久久久久国产精品人妻一区二区| 国产成人精品在线电影| 中文字幕最新亚洲高清| 亚洲av在线观看美女高潮| 国产成人精品久久久久久| 91久久精品国产一区二区三区| 啦啦啦啦在线视频资源| 国产精品久久久久久久电影| 亚洲内射少妇av| 国产日韩欧美视频二区| 在线天堂最新版资源| 高清av免费在线| 九色亚洲精品在线播放| .国产精品久久| 精品午夜福利在线看| 51国产日韩欧美| 99re6热这里在线精品视频| 亚洲欧美成人综合另类久久久| 美女cb高潮喷水在线观看| 久久这里有精品视频免费| 国产黄频视频在线观看| 国产精品熟女久久久久浪| 日韩在线高清观看一区二区三区| 日本vs欧美在线观看视频| 黄色视频在线播放观看不卡| 女性生殖器流出的白浆| 夫妻午夜视频| av黄色大香蕉| 日产精品乱码卡一卡2卡三| 高清不卡的av网站| 国产午夜精品一二区理论片| 七月丁香在线播放| 建设人人有责人人尽责人人享有的| 欧美激情极品国产一区二区三区 | 久久久久网色| 国产成人精品福利久久| 欧美国产精品一级二级三级| 亚洲图色成人| av播播在线观看一区| 99九九在线精品视频| 日韩精品免费视频一区二区三区 | 一本色道久久久久久精品综合| 午夜激情福利司机影院| 全区人妻精品视频| 久久精品久久精品一区二区三区| 日韩一区二区视频免费看| 日本av免费视频播放| 国模一区二区三区四区视频| 成人午夜精彩视频在线观看| 七月丁香在线播放| 欧美成人精品欧美一级黄| 熟女电影av网| 一区二区三区四区激情视频| 一区二区日韩欧美中文字幕 | av又黄又爽大尺度在线免费看| 久久99热6这里只有精品| 女人久久www免费人成看片| 国产精品三级大全| 久久久久久久亚洲中文字幕| 日本wwww免费看| 亚洲欧美日韩另类电影网站| 大话2 男鬼变身卡| 国产成人a∨麻豆精品| 一区二区日韩欧美中文字幕 | 男女边吃奶边做爰视频| 99久久人妻综合| 婷婷色麻豆天堂久久| 性色avwww在线观看| 亚洲无线观看免费| 精品久久久久久久久av| 国产亚洲精品第一综合不卡 | 免费观看性生交大片5| 欧美97在线视频| 欧美bdsm另类| 免费看av在线观看网站| 国产黄色免费在线视频| 简卡轻食公司| 高清午夜精品一区二区三区| 日日摸夜夜添夜夜爱| 亚洲精品久久成人aⅴ小说 | 午夜精品国产一区二区电影| 久久免费观看电影| 日韩亚洲欧美综合| 久久久久久久久久人人人人人人| 黄色怎么调成土黄色| 国产色婷婷99| 免费不卡的大黄色大毛片视频在线观看| 亚洲av综合色区一区| 国产成人精品无人区| 黄色毛片三级朝国网站| 亚洲性久久影院| 国产精品国产三级国产av玫瑰| 日韩一区二区三区影片| 成人免费观看视频高清| 女性生殖器流出的白浆| 只有这里有精品99| 国内精品宾馆在线| 黄色一级大片看看| 国产精品国产三级国产av玫瑰| 久久 成人 亚洲| 97超碰精品成人国产| 国产黄频视频在线观看| av电影中文网址| 亚洲精品美女久久av网站| 少妇人妻 视频| 久久国内精品自在自线图片| 赤兔流量卡办理| 97超视频在线观看视频| 日韩一区二区三区影片| 尾随美女入室| 又粗又硬又长又爽又黄的视频| 人妻少妇偷人精品九色| 在线精品无人区一区二区三| 狂野欧美激情性xxxx在线观看| 香蕉精品网在线| 成人免费观看视频高清| 成人国产av品久久久| 久热这里只有精品99| 男女啪啪激烈高潮av片| 高清不卡的av网站| 三上悠亚av全集在线观看| 国产精品久久久久久久电影| 欧美国产精品一级二级三级| 99热这里只有精品一区| 欧美日韩在线观看h| 91精品伊人久久大香线蕉| 久久精品国产亚洲av天美| 国产黄频视频在线观看| 插阴视频在线观看视频| 免费少妇av软件| 永久网站在线| 美女xxoo啪啪120秒动态图| 欧美3d第一页| 天天操日日干夜夜撸| 国国产精品蜜臀av免费| 久热久热在线精品观看| 国产女主播在线喷水免费视频网站| 亚洲高清免费不卡视频| 亚洲丝袜综合中文字幕| av免费观看日本| 美女xxoo啪啪120秒动态图| 久久婷婷青草| 欧美人与性动交α欧美精品济南到 | 国产免费视频播放在线视频| 日韩精品免费视频一区二区三区 | 中文天堂在线官网| 最后的刺客免费高清国语| 黑人巨大精品欧美一区二区蜜桃 | 国产69精品久久久久777片| 伦精品一区二区三区| 亚洲精品乱码久久久久久按摩| 老司机影院成人| 另类亚洲欧美激情| 免费播放大片免费观看视频在线观看| 亚洲国产色片| 制服丝袜香蕉在线| 久久综合国产亚洲精品| 丝袜喷水一区| 国产一区二区在线观看av| 国产精品熟女久久久久浪| 亚洲人成网站在线观看播放| 免费久久久久久久精品成人欧美视频 | 亚洲美女黄色视频免费看| 欧美日韩视频高清一区二区三区二| 18+在线观看网站| 3wmmmm亚洲av在线观看| 国产黄色视频一区二区在线观看| 人妻夜夜爽99麻豆av| 搡老乐熟女国产| 中文字幕亚洲精品专区| 纵有疾风起免费观看全集完整版| 免费观看的影片在线观看| kizo精华| av又黄又爽大尺度在线免费看| 91成人精品电影| 视频在线观看一区二区三区| 能在线免费看毛片的网站| 免费人成在线观看视频色| 一本色道久久久久久精品综合| 亚洲精品第二区| 国产在线视频一区二区| 国产一区亚洲一区在线观看| 欧美亚洲日本最大视频资源| 久久人妻熟女aⅴ| 成人漫画全彩无遮挡| 亚洲人成网站在线播| 亚洲天堂av无毛| 免费观看的影片在线观看| 日韩成人伦理影院| 久久久久久伊人网av| 老熟女久久久| 免费高清在线观看视频在线观看| 日韩免费高清中文字幕av| 成年人免费黄色播放视频| 亚洲精品乱久久久久久| 18禁观看日本| 久久精品久久久久久噜噜老黄| 中文乱码字字幕精品一区二区三区| 国产欧美亚洲国产| 亚洲国产av影院在线观看| 18禁观看日本| 最新的欧美精品一区二区| 大片免费播放器 马上看| 岛国毛片在线播放| 男女高潮啪啪啪动态图| 国产成人aa在线观看| 全区人妻精品视频| xxxhd国产人妻xxx| 国产色婷婷99| 蜜臀久久99精品久久宅男| 在线免费观看不下载黄p国产| 亚洲经典国产精华液单| 成人18禁高潮啪啪吃奶动态图 | 91久久精品电影网| √禁漫天堂资源中文www| 久久精品国产a三级三级三级| 亚洲av欧美aⅴ国产| 精品一区二区三区视频在线| 久久精品人人爽人人爽视色| 一级毛片电影观看| 久久精品国产鲁丝片午夜精品| 亚洲精品亚洲一区二区| 国产精品国产三级国产专区5o| 欧美日韩综合久久久久久| 黑人欧美特级aaaaaa片| 日韩一区二区视频免费看| 日本vs欧美在线观看视频| 97精品久久久久久久久久精品| 免费人成在线观看视频色| 男女边吃奶边做爰视频| 精品亚洲成国产av| 亚洲天堂av无毛| 亚洲精品国产av蜜桃| 精品人妻偷拍中文字幕| 亚洲综合精品二区| 亚洲第一区二区三区不卡| 久久精品久久精品一区二区三区| 免费av不卡在线播放| 久久午夜福利片| 在线天堂最新版资源| 老司机亚洲免费影院| 天天影视国产精品| 精品久久国产蜜桃| 欧美精品高潮呻吟av久久| 亚州av有码| 99热这里只有精品一区| 国产精品一国产av| 三上悠亚av全集在线观看| 日韩av不卡免费在线播放| 免费大片18禁| av有码第一页| 久久综合国产亚洲精品| 日韩电影二区| 9色porny在线观看| 久久久精品免费免费高清| 亚洲国产精品一区三区| 成人综合一区亚洲| 亚洲av成人精品一二三区| 国产乱人偷精品视频| 欧美精品一区二区免费开放| 水蜜桃什么品种好| 日韩av不卡免费在线播放| 一区二区三区乱码不卡18| 日日摸夜夜添夜夜添av毛片| 免费大片18禁| 两个人免费观看高清视频| 26uuu在线亚洲综合色| 97在线人人人人妻| 日韩中字成人| 水蜜桃什么品种好| 欧美日韩视频精品一区| 麻豆精品久久久久久蜜桃| 如日韩欧美国产精品一区二区三区 | 春色校园在线视频观看| 99国产精品免费福利视频| 亚洲国产av影院在线观看| 热re99久久国产66热| 亚洲综合色网址| 简卡轻食公司| 国产精品人妻久久久久久| 久久久久久伊人网av| 免费日韩欧美在线观看| 国产精品国产av在线观看| 久久久久精品久久久久真实原创| 在现免费观看毛片| 一级毛片aaaaaa免费看小| 欧美亚洲 丝袜 人妻 在线| 狂野欧美激情性xxxx在线观看| 久久久精品区二区三区| 99国产精品免费福利视频| 五月伊人婷婷丁香| 一区二区三区免费毛片| 亚洲国产av影院在线观看| 一本色道久久久久久精品综合| 在线精品无人区一区二区三| 色94色欧美一区二区| 亚洲国产av新网站| 日韩成人av中文字幕在线观看| 中文字幕亚洲精品专区| 久久精品人人爽人人爽视色| 国产精品欧美亚洲77777| 99热这里只有是精品在线观看| 狠狠婷婷综合久久久久久88av| 国产精品欧美亚洲77777| 三上悠亚av全集在线观看| 国产成人精品久久久久久| 欧美日韩视频高清一区二区三区二| 久久精品国产亚洲av天美| 日韩一本色道免费dvd| 美女内射精品一级片tv| a级片在线免费高清观看视频| 99久久中文字幕三级久久日本| 久久狼人影院| 丰满迷人的少妇在线观看| 99国产精品免费福利视频| 成人影院久久| 成人综合一区亚洲| 国产精品不卡视频一区二区| 人成视频在线观看免费观看| 中文字幕av电影在线播放| 精品人妻熟女毛片av久久网站| 国产精品女同一区二区软件| 一级毛片aaaaaa免费看小| 久久久久久伊人网av| 蜜桃国产av成人99| 欧美精品人与动牲交sv欧美| 在现免费观看毛片| 黑丝袜美女国产一区| 一区二区三区免费毛片| 欧美日本中文国产一区发布| 制服人妻中文乱码| 99久久精品一区二区三区| 亚洲欧美成人综合另类久久久| 精品人妻熟女av久视频| 国产免费福利视频在线观看| 综合色丁香网| 成年女人在线观看亚洲视频| 一区在线观看完整版| 一边摸一边做爽爽视频免费| 成人毛片60女人毛片免费| 一本久久精品| 久久久久久久久久久免费av| 欧美国产精品一级二级三级| 18禁观看日本| 日产精品乱码卡一卡2卡三| 精品少妇内射三级| 免费看不卡的av| 亚州av有码| 97在线人人人人妻| 美女主播在线视频| 国产精品99久久99久久久不卡 | av网站免费在线观看视频| 日日爽夜夜爽网站| 考比视频在线观看| 亚洲天堂av无毛| 中文乱码字字幕精品一区二区三区| 女人久久www免费人成看片| 久久综合国产亚洲精品| 国产淫语在线视频| 爱豆传媒免费全集在线观看| 狠狠精品人妻久久久久久综合| av播播在线观看一区| 男人爽女人下面视频在线观看| 看十八女毛片水多多多| 成人漫画全彩无遮挡| av视频免费观看在线观看| 女人精品久久久久毛片| 欧美成人午夜免费资源| 亚洲精品日韩av片在线观看| 黄色视频在线播放观看不卡| 插逼视频在线观看| 啦啦啦中文免费视频观看日本| 亚洲无线观看免费| 日韩中文字幕视频在线看片| 啦啦啦啦在线视频资源| 全区人妻精品视频| 亚洲精品av麻豆狂野| 一级毛片aaaaaa免费看小| 亚洲av成人精品一二三区| 日本黄色片子视频| 免费av不卡在线播放| 在线观看国产h片| 午夜影院在线不卡| 亚洲精品亚洲一区二区| 91精品伊人久久大香线蕉| 国产精品一区二区三区四区免费观看| 多毛熟女@视频| 欧美精品高潮呻吟av久久| 一区二区av电影网| 午夜精品国产一区二区电影| 99热国产这里只有精品6| 韩国av在线不卡| 亚洲av国产av综合av卡| av不卡在线播放| 天堂中文最新版在线下载| 777米奇影视久久| 国产69精品久久久久777片| 成人毛片60女人毛片免费| 春色校园在线视频观看| 成人免费观看视频高清| 美女xxoo啪啪120秒动态图| 两个人免费观看高清视频| 97超视频在线观看视频| 久久久久久人妻| 搡女人真爽免费视频火全软件| 国产一级毛片在线| 制服诱惑二区| 美女视频免费永久观看网站| av在线观看视频网站免费| 人妻系列 视频| 日韩人妻高清精品专区| av卡一久久| 亚洲中文av在线| 久久 成人 亚洲| 久久久久国产网址| 91久久精品国产一区二区成人| 黑丝袜美女国产一区| 99久国产av精品国产电影| 亚洲av日韩在线播放| 久久国内精品自在自线图片| 交换朋友夫妻互换小说| 久久久久网色| 亚洲av中文av极速乱| 国产亚洲一区二区精品| 国产精品一国产av| 国产一级毛片在线| 美女主播在线视频| 亚洲精品乱码久久久v下载方式| av免费观看日本| 18禁动态无遮挡网站| 亚洲精品自拍成人| 亚洲国产精品成人久久小说| 91久久精品电影网| 国产精品99久久99久久久不卡 | .国产精品久久| 一区二区三区免费毛片| 肉色欧美久久久久久久蜜桃| 日韩亚洲欧美综合| 成人毛片a级毛片在线播放| 一级黄片播放器| 在线观看免费日韩欧美大片 | 熟女电影av网| 亚洲成人手机| 欧美+日韩+精品| 色视频在线一区二区三区| 麻豆成人av视频| 亚洲国产精品一区三区| 一级毛片aaaaaa免费看小| 夫妻午夜视频|