Prediction value of long noncoding RNA H19 and HOTTIP on therapeutic effect of neoadjuvant chemotherapy for resectable locally advanced gastric cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIU Chuanxu ¹ , JIAN Mi ² , YAO Zengwu ² , HU Jinchen ² , CUI Hongming ¹ , YU Bin ¹ , ZHAO Yang ² ,  JIANG Lixin ²

1. Qingdao University, Qingdao, Shandong 264000, P. R. China;
2. The First Department of Gastrointestinal Surgery, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P. R. China;

Corresponding author：

JIANG Lixin, Email: jianglixin1969@hotmail.com

Keywords：

long noncoding RNA; H19; HOTTIP; neoadjuvant chemotherapy; advanced gastric cancer

DOI：

10.7507/1007-9424.202105019

Video：

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Objective To study value of long noncoding RNA H19 and HOTTIP in plasma in predicting efficacy of neoadjuvant chemotherapy (NAC) for resectable locally advanced gastric cancer. Methods Forty patients with T3–4aN⁺M0 gastric cancer and 40 patients with benign gastric diseases treated in the Yantai Yuhuangding Hospital Affiliated to Qingdao University from August 2020 to May 2021 were prospectively included. The expressions of H19 and HOTTIP in the plasma of gastric cancer and benign gastric diseases patients without any treatment after admission were detected before treatment (CAPEOX regimen was used in the patients with gastric cancer), then which were detected after 2 NAC courses for patients with gastric cancer. Meanwhile, some clinical items were detected and the efficacy of NAC was evaluated. The complete remission (CR) and partial remission (PR) were classified as objective remission, CR, PR, and disease stability were classified as disease control. The expressions of H19 and HOTTIP between the different patients were compared and the receiver operating characteristic (ROC) curve was used to evaluate their values in the diagnosis of resectable locally advanced gastric cancer. Results There were 13 cases of T downstaging and 27 cases of T non-downstaging and 25 cases of objective remission and 35 disease control after NAC. The median relative expression levels of H19 and HOTTIP before NAC in the patients with gastric cancer were higher than those in the patients with benign gastric diseases (H19: 1.42 versus 0.98, Z=–3.835, P<0.001; HOTTIP: 2.15 versus 1.04, Z=–5.062, P<0.001), and which were in the patients with T downstaging and disease control were lower than those in the patients with T non-downstaging and 5 cases of disease progression (For T staging, H19: 1.12 versus 1.54, Z=–2.960, P=0.002; HOTTIP: 1.49 versus 2.30, Z=–2.310, P=0.019. For efficacy of NAC, H19: 1.39 versus 2.48, Z=–3.211, P<0.001; HOTTIP: 1.96 versus 3.25, Z=–2.393, P=0.014). The median relative expressions of H19 and HOTTIP after NAC were lower than those before NAC in the patients with gastric cancer (H19: 1.12 versus 1.42, Z=–3.965, P<0.001; HOTTIP: 1.30 versus 2.15, Z=–4.839, P<0.001). There were no significant differences in the changes of H19 and HOTTIP before and after NAC between the patients with T downstaging and T non-downstaging, and between disease control and disease progression (P>0.05). The areas of ROC curve of H19, HOTTIP, and combination of H19 and HOTTIP in diagnosis of resectable locally advanced gastric cancer were higher than 0.7. Conclusions LncRNA H19 and HOTTIP might be potential tumor markers in gastric cancer, and their diagnostic values for resectable locally advanced gastric cancer are higher. Gastric cancer patients with low expressions of H19 and HOTTIP in plasma might be more sensitive to NAC.

Citation： LIU Chuanxu, JIAN Mi, YAO Zengwu, HU Jinchen, CUI Hongming, YU Bin, ZHAO Yang, JIANG Lixin. Prediction value of long noncoding RNA H19 and HOTTIP on therapeutic effect of neoadjuvant chemotherapy for resectable locally advanced gastric cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(1): 59-66. doi: 10.7507/1007-9424.202105019 Copy

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2.	苗儒林, 李子禹, 季加孚. 从中国胃肠肿瘤外科联盟相关数据分析我国早期胃癌诊治现状和发展趋势. 中国实用外科杂志, 2019, 39(5): 419-423.
3.	王玮, 孙哲, 邓靖宇, 等. 基于多中心大样本数据库的胃癌外科治疗相关数据的整合与分析. 中华胃肠外科杂志, 2016, 19(2): 185.
4.	Necula L, Matei L, Dragu D, et al. Recent advances in gastric cancer early diagnosis. World J Gastroenterol, 2019, 25(17): 2029-2044.
5.	Sun W, Yang Y, Xu C, et al. Roles of long noncoding RNAs in gastric cancer and their clinical applications. J Cancer Res Clin Oncol, 2016, 142(11): 2231-2237.
6.	Yörüker EE, Keskin M, Kulle CB, et al. Diagnostic and prognostic value of circulating lncRNA H19 in gastric cancer. Biomed Rep, 2018, 9(2): 181-186.
7.	Yang Z, Sun Y, Liu R, et al. Plasma long noncoding RNAs PANDAR, FOXD2-AS1, and SMARCC2 as potential novel diagnostic biomarkers for gastric cancer. Cancer Manag Res, 2019, 11: 6175-6184.
8.	Zhao R, Zhang Y, Zhang X, et al. Exosomal long noncoding RNA HOTTIP as potential novel diagnostic and prognostic biomarker test for gastric cancer. Mol Cancer, 2018, 17(1): 68.
9.	Ye H, Liu K, Qian K. Overexpression of long noncoding RNA HOTTIP promotes tumor invasion and predicts poor prognosis in gastric cancer. Onco Targets Ther, 2016, 9: 2081-2088.
10.	Mao Z, Wu Y, Zhou J, et al. Salinomycin reduces epithelial-mesenchymal transition-mediated multidrug resistance by modifying long noncoding RNA HOTTIP expression in gastric cancer cells. Anticancer Drugs, 2019, 30(9): 892-899.
11.	Sun F, Liang W, Qian J. The identification of CRNDE, H19, UCA1 and HOTAIR as the key lncRNAs involved in oxaliplatin or irinotecan resistance in the chemotherapy of colorectal cancer based on integrative bioinformatics analysis. Mol Med Rep, 2019, 20(4): 3583-3596.
12.	Choi AH, Kim J, Chao J. Perioperative chemotherapy for resectable gastric cancer: MAGIC and beyond. World J Gastroenterol, 2015, 21(24): 7343-7348.
13.	Schwartz LH, Litière S, de Vries E, et al. RECIST 1.1—Update and clarification: from the RECIST committee. Eur J Cancer, 2016, 62: 132-137.
14.	Charruf AZ, Ramos MFKP, Pereira MA, et al. Impact of neoadjuvant chemotherapy on surgical and pathological results of gastric cancer patients: a case-control study. J Surg Oncol, 2020, 121(5): 833-839.
15.	Reddavid R, Sofia S, Chiaro P, et al. Neoadjuvant chemotherapy for gastric cancer. Is it a must or a fake? World J Gastroenterol, 2018, 24(2): 274-289.
16.	Liu R, Zeng Y, Zhou CF, et al. Long noncoding RNA expression signature to predict platinum-based chemotherapeutic sensitivity of ovarian cancer patients. Sci Rep, 2017, 7(1): 18.
17.	Jiang L, Wang W, Li G, et al. High TUG1 expression is associated with chemotherapy resistance and poor prognosis in esophageal squamous cell carcinoma. Cancer Chemother Pharmacol, 2016, 78(2): 333-339.
18.	Engreitz JM, Haines JE, Perez EM, et al. Local regulation of gene expression by lncRNA promoters, transcription and splicing. Nature, 2016, 539(7629): 452-455.
19.	Xu W, Zhou G, Wang H, et al. Circulating lncRNA SNHG11 as a novel biomarker for early diagnosis and prognosis of colorectal cancer. Int J Cancer, 2020, 146(10): 2901-2912.
20.	Abdi E, Latifi-Navid S, Abdi F, et al. Emerging circulating miRNAs and lncRNAs in upper gastrointestinal cancers. Expert Rev Mol Diagn, 2020, 20(11): 1121-1138.
21.	Liu G, Xiang T, Wu QF, et al. Long noncoding RNA H19-derived miR-675 enhances proliferation and invasion via RUNX1 in gastric cancer cells. Oncol Res, 2016, 23(3): 99-107.
22.	Fan Y, Yan T, Chai Y, et al. Long noncoding RNA HOTTIP as an independent prognostic marker in cancer. Clin Chim Acta, 2018, 482: 224-230.
23.	Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell, 2011, 43(6): 904-914.
24.	Chang S, Liu J, Guo S, et al. HOTTIP and HOXA13 are oncogenes associated with gastric cancer progression. Oncol Rep, 2016, 35(6): 3577-3585.
25.	Ye Y, Shen A, Liu A. Long non-coding RNA H19 and cancer: a competing endogenous RNA. Bull Cancer, 2019, 106(12): 1152-1159.
26.	Ali Akbar-Esfahani S, Karimipoor M, Bahreini F, et al. Diagnostic value of plasma long non-coding RNA HOTTIP as a non-invasive biomarker for colorectal cancer (a case-control study). Int J Mol Cell Med, 2019, 8(4): 240-247.
27.	Wang Y, Li Z, Zheng S, et al. Expression profile of long non-coding RNAs in pancreatic cancer and their clinical significance as biomarkers. Oncotarget, 2015, 6(34): 35684-35698.
28.	Wang J, Sun J, Yang F. The role of long non-coding RNA H19 in breast cancer. Oncol Lett, 2020, 19(1): 7-16.
29.	Zhao R, Zhang X, Zhang Y, et al. HOTTIP predicts poor survival in gastric cancer patients and contributes to cisplatin resistance by sponging miR-216a-5p. Front Cell Dev Biol, 2020, 8: 348.
30.	Wang J, Ma X, Si H, et al. Role of long non-coding RNA H19 in therapy resistance of digestive system cancers. Mol Med, 2021, 27(1): 1.
31.	Choi RS, Lai WYX, Lee LTC, et al. Current and future molecular diagnostics of gastric cancer. Expert Rev Mol Diagn, 2019, 19(10): 863-874.
32.	Gao S, Zhao ZY, Wu R, et al. Prognostic value of long noncoding RNAs in gastric cancer: a meta-analysis. Onco Targets Ther, 2018, 11: 4877-4891.
33.	Ding K, Liao Y, Gong D, et al. Effect of long non-coding RNA H19 on oxidative stress and chemotherapy resistance of CD133⁺ cancer stem cells via the MAPK/ERK signaling pathway in hepatocellular carcinoma. Biochem Biophys Res Commun, 2018, 502(2): 194-201.
34.	Yu S, Wu C, Tan Q, et al. Long noncoding RNA H19 promotes chemotherapy resistance in choriocarcinoma cells. J Cell Biochem, 2019, 120(9): 15131-15144.
35.	Pattingre S, Levine B. Bcl-2 inhibition of autophagy: a new route to cancer? Cancer Res, 2006, 66(6): 2885-2888.
36.	Valente G, Morani F, Nicotra G, et al. Expression and clinical significance of the autophagy proteins BECLIN 1 and LC3 in ovarian cancer. Biomed Res Int, 2014, 2014: 462658.
37.	Chen JS, Wang YF, Zhang XQ, et al. H19 serves as a diagnostic biomarker and up-regulation of H19 expression contributes to poor prognosis in patients with gastric cancer. Neoplasma, 2016, 63(2): 223-230.
38.	Yu J, Fang C, Zhang Z, et al. H19 rises in gastric cancer and exerts a tumor-promoting function via miR-138/ E2F2 axis. Cancer Manag Res, 2020, 12: 13033-13042.

1. den Hoed CM, Kuipers EJ. Gastric cancer: How can we reduce the incidence of this disease? Curr Gastroenterol Rep, 2016, 18(7): 34.
2. 苗儒林, 李子禹, 季加孚. 从中国胃肠肿瘤外科联盟相关数据分析我国早期胃癌诊治现状和发展趋势. 中国实用外科杂志, 2019, 39(5): 419-423.
3. 王玮, 孙哲, 邓靖宇, 等. 基于多中心大样本数据库的胃癌外科治疗相关数据的整合与分析. 中华胃肠外科杂志, 2016, 19(2): 185.
4. Necula L, Matei L, Dragu D, et al. Recent advances in gastric cancer early diagnosis. World J Gastroenterol, 2019, 25(17): 2029-2044.
5. Sun W, Yang Y, Xu C, et al. Roles of long noncoding RNAs in gastric cancer and their clinical applications. J Cancer Res Clin Oncol, 2016, 142(11): 2231-2237.
6. Yörüker EE, Keskin M, Kulle CB, et al. Diagnostic and prognostic value of circulating lncRNA H19 in gastric cancer. Biomed Rep, 2018, 9(2): 181-186.
7. Yang Z, Sun Y, Liu R, et al. Plasma long noncoding RNAs PANDAR, FOXD2-AS1, and SMARCC2 as potential novel diagnostic biomarkers for gastric cancer. Cancer Manag Res, 2019, 11: 6175-6184.
8. Zhao R, Zhang Y, Zhang X, et al. Exosomal long noncoding RNA HOTTIP as potential novel diagnostic and prognostic biomarker test for gastric cancer. Mol Cancer, 2018, 17(1): 68.
9. Ye H, Liu K, Qian K. Overexpression of long noncoding RNA HOTTIP promotes tumor invasion and predicts poor prognosis in gastric cancer. Onco Targets Ther, 2016, 9: 2081-2088.
10. Mao Z, Wu Y, Zhou J, et al. Salinomycin reduces epithelial-mesenchymal transition-mediated multidrug resistance by modifying long noncoding RNA HOTTIP expression in gastric cancer cells. Anticancer Drugs, 2019, 30(9): 892-899.
11. Sun F, Liang W, Qian J. The identification of CRNDE, H19, UCA1 and HOTAIR as the key lncRNAs involved in oxaliplatin or irinotecan resistance in the chemotherapy of colorectal cancer based on integrative bioinformatics analysis. Mol Med Rep, 2019, 20(4): 3583-3596.
12. Choi AH, Kim J, Chao J. Perioperative chemotherapy for resectable gastric cancer: MAGIC and beyond. World J Gastroenterol, 2015, 21(24): 7343-7348.
13. Schwartz LH, Litière S, de Vries E, et al. RECIST 1.1—Update and clarification: from the RECIST committee. Eur J Cancer, 2016, 62: 132-137.
14. Charruf AZ, Ramos MFKP, Pereira MA, et al. Impact of neoadjuvant chemotherapy on surgical and pathological results of gastric cancer patients: a case-control study. J Surg Oncol, 2020, 121(5): 833-839.
15. Reddavid R, Sofia S, Chiaro P, et al. Neoadjuvant chemotherapy for gastric cancer. Is it a must or a fake? World J Gastroenterol, 2018, 24(2): 274-289.
16. Liu R, Zeng Y, Zhou CF, et al. Long noncoding RNA expression signature to predict platinum-based chemotherapeutic sensitivity of ovarian cancer patients. Sci Rep, 2017, 7(1): 18.
17. Jiang L, Wang W, Li G, et al. High TUG1 expression is associated with chemotherapy resistance and poor prognosis in esophageal squamous cell carcinoma. Cancer Chemother Pharmacol, 2016, 78(2): 333-339.
18. Engreitz JM, Haines JE, Perez EM, et al. Local regulation of gene expression by lncRNA promoters, transcription and splicing. Nature, 2016, 539(7629): 452-455.
19. Xu W, Zhou G, Wang H, et al. Circulating lncRNA SNHG11 as a novel biomarker for early diagnosis and prognosis of colorectal cancer. Int J Cancer, 2020, 146(10): 2901-2912.
20. Abdi E, Latifi-Navid S, Abdi F, et al. Emerging circulating miRNAs and lncRNAs in upper gastrointestinal cancers. Expert Rev Mol Diagn, 2020, 20(11): 1121-1138.
21. Liu G, Xiang T, Wu QF, et al. Long noncoding RNA H19-derived miR-675 enhances proliferation and invasion via RUNX1 in gastric cancer cells. Oncol Res, 2016, 23(3): 99-107.
22. Fan Y, Yan T, Chai Y, et al. Long noncoding RNA HOTTIP as an independent prognostic marker in cancer. Clin Chim Acta, 2018, 482: 224-230.
23. Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell, 2011, 43(6): 904-914.
24. Chang S, Liu J, Guo S, et al. HOTTIP and HOXA13 are oncogenes associated with gastric cancer progression. Oncol Rep, 2016, 35(6): 3577-3585.
25. Ye Y, Shen A, Liu A. Long non-coding RNA H19 and cancer: a competing endogenous RNA. Bull Cancer, 2019, 106(12): 1152-1159.
26. Ali Akbar-Esfahani S, Karimipoor M, Bahreini F, et al. Diagnostic value of plasma long non-coding RNA HOTTIP as a non-invasive biomarker for colorectal cancer (a case-control study). Int J Mol Cell Med, 2019, 8(4): 240-247.
27. Wang Y, Li Z, Zheng S, et al. Expression profile of long non-coding RNAs in pancreatic cancer and their clinical significance as biomarkers. Oncotarget, 2015, 6(34): 35684-35698.
28. Wang J, Sun J, Yang F. The role of long non-coding RNA H19 in breast cancer. Oncol Lett, 2020, 19(1): 7-16.
29. Zhao R, Zhang X, Zhang Y, et al. HOTTIP predicts poor survival in gastric cancer patients and contributes to cisplatin resistance by sponging miR-216a-5p. Front Cell Dev Biol, 2020, 8: 348.
30. Wang J, Ma X, Si H, et al. Role of long non-coding RNA H19 in therapy resistance of digestive system cancers. Mol Med, 2021, 27(1): 1.
31. Choi RS, Lai WYX, Lee LTC, et al. Current and future molecular diagnostics of gastric cancer. Expert Rev Mol Diagn, 2019, 19(10): 863-874.
32. Gao S, Zhao ZY, Wu R, et al. Prognostic value of long noncoding RNAs in gastric cancer: a meta-analysis. Onco Targets Ther, 2018, 11: 4877-4891.
33. Ding K, Liao Y, Gong D, et al. Effect of long non-coding RNA H19 on oxidative stress and chemotherapy resistance of CD133⁺ cancer stem cells via the MAPK/ERK signaling pathway in hepatocellular carcinoma. Biochem Biophys Res Commun, 2018, 502(2): 194-201.
34. Yu S, Wu C, Tan Q, et al. Long noncoding RNA H19 promotes chemotherapy resistance in choriocarcinoma cells. J Cell Biochem, 2019, 120(9): 15131-15144.
35. Pattingre S, Levine B. Bcl-2 inhibition of autophagy: a new route to cancer? Cancer Res, 2006, 66(6): 2885-2888.
36. Valente G, Morani F, Nicotra G, et al. Expression and clinical significance of the autophagy proteins BECLIN 1 and LC3 in ovarian cancer. Biomed Res Int, 2014, 2014: 462658.
37. Chen JS, Wang YF, Zhang XQ, et al. H19 serves as a diagnostic biomarker and up-regulation of H19 expression contributes to poor prognosis in patients with gastric cancer. Neoplasma, 2016, 63(2): 223-230.
38. Yu J, Fang C, Zhang Z, et al. H19 rises in gastric cancer and exerts a tumor-promoting function via miR-138/ E2F2 axis. Cancer Manag Res, 2020, 12: 13033-13042.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Prediction value of long noncoding RNA H19 and HOTTIP on therapeutic effect of neoadjuvant chemotherapy for resectable locally advanced gastric cancer

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