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Year : 2019  |  Volume : 15  |  Issue : 4  |  Page : 933-940

Correlation between long non-coding RNAs (lncRNAs) H19 expression and trastuzumab resistance in breast cancer

Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China

Date of Web Publication14-Aug-2019

Correspondence Address:
Ying Guo
Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, Huaiyin, Jinan 250021
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_208_19

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 > Abstract 

Introduction: Trastuzumab resistance is a major obstacle encountered in human epidermal growth factor receptor 2 (HER2)-positive breast cancer therapy. Long non-coding RNAs (lncRNAs) have been confirmed to play important roles in both tumorigenesis and tumor development. However, whether lncRNAs are associated with trastuzumab resistance is not yet clear.
Subjects and Methods: We evaluated trastuzumab sensitivity in breast cancer cell lines, SKBR3, HCC1954, and MDA-MB-231. We also evaluated H19 expression in these cell lines after treatment with different trastuzumab concentrations. Besides, H19 was downregulated to investigate its role in cell viability and trastuzumab sensitivity and a trastuzumab resistance cell line was cultured to verify the effect of H19 in trastuzumab resistance. Forty-eight HER2-positive breast cancer patients treated with trastuzumab in the first-line setting were selected retrospectively to explore the relationship between H19 expression and tumor-node-metastasis (TNM) stage as well as trastuzumab resistance.
Results: H19 is a trastuzumab-responsive lncRNA and its expression was upregulated in a trastuzumab-resistant breast cancer cell. Downregulation of H19 restored the sensitivity of trastuzumab-resistant cells to this drug. The expression of H19 significantly correlated with TNM stage. Patients with higher expression of H19 showed an evidently shorter progression-free survival than those with low H19 expression. H19 overexpression was negatively correlated to the trastuzumab-therapy response.
Conclusions: Our results provide evidence for the H19-mediated regulation of trastuzumab resistance in HER2-positive breast cancer cells. H19 could act as a potential predictive biomarker for HER2-positive breast cancer patients, and downregulation of H19 could reverse trastuzumab resistance and enhance the inhibitory function of this drug.

Keywords: Breast cancer, H19, human epidermal growth factor receptor 2, resistance, trastuzumab

How to cite this article:
Sun Z, Zhang C, Wang T, Shi P, Tian X, Guo Y. Correlation between long non-coding RNAs (lncRNAs) H19 expression and trastuzumab resistance in breast cancer. J Can Res Ther 2019;15:933-40

How to cite this URL:
Sun Z, Zhang C, Wang T, Shi P, Tian X, Guo Y. Correlation between long non-coding RNAs (lncRNAs) H19 expression and trastuzumab resistance in breast cancer. J Can Res Ther [serial online] 2019 [cited 2020 Sep 18];15:933-40. Available from: http://www.cancerjournal.net/text.asp?2019/15/4/933/264281

 > Introduction Top

Breast cancer is a heterogeneous and complex neoplasm that accounts for 25% of all cancers and for 15% of cancer-related deaths in females worldwide.[1] Breast cancer is the most common malignancy among women leading to serious sequelae on the health-related quality of life.[2] Nearly 25%–30% of breast cancer tissues exhibit human epidermal growth factor receptor 2 (HER2) overexpression or gene amplification, and are characterized with high chemotherapy resistance, cell malignancy, metastasis, and poor prognosis.[3],[4] Trastuzumab, the first antibody that is widely applied in anti-HER2 targeted treatment, notably enhanced the overall survival of HER2-positive breast cancer patients. Despite the survival benefit offered by trastuzumab-therapy, advanced HER2-positive breast cancer patients displayed primary resistance to anti-HER2 therapies, and though they responded initially, they acquired trastuzumab resistance later on.[5] Hence, identifying the causes of resistance is warranted. Unfortunately, the identified potential mechanisms do not coincide with the frequent occurrence of trastuzumab resistance, and no effective biomarkers have been approved to predict and target trastuzumab resistance. Therefore, a better understanding of the underlying mechanisms of trastuzumab resistance is critical for improving HER2-positive breast cancer treatment.

Immunohistochemical analyses of topoisomerase 2-alpha, tissue inhibitors of metalloproteinases-1, and B-tub expressions are could be used for the prediction of tumor responses to chemotherapy.[6] Many critical biological processes, including survival, cell growth, invasion, migration, and differentiation are regulated by long non-coding RNAs (lncRNAs). H19 is located at 11p 15.5 in humans and is highly expressed in the embryo, the fetal tissues, and the extraembryonic tissue. After birth, H19 expression is suppressed, although a basal expression exists in several organs, including the uterus and adrenal and mammary glands.[7],[8] H19 is an imprinted, conserved, and highly abundant lncRNA in several cancers. H19 serves as a tumor suppressor factor in Bechwith–Wiedemann syndrome, rhabdomyosarcoma, and Wilm's tumors.[9] Nevertheless, numerous studies have demonstrated that H19 acts as an oncogene in several types of tumors. H19 overexpression is frequently related to poor prognosis in gastric, lung, esophageal, and bladder tumors.[10],[11],[12],[13],[14] H19 has been reported to be overexpressed in 70% of breast cancers.[15] Furthermore, in mammary epithelial cells, overexpression of H19 promoted tumorigenesis through upregulation of thioredoxin, transcription factors, such as E2F1, and growth factors, such as hepatocyte growth factor (HGF), to promote cell cycle progression and cell invasion.[16],[17] These findings indicate the oncogenic role of H19 in breast tumor.[18] We hypothesize that H19 might play a vital role in HER2 receptor stabilization and other tyrosine kinase receptors that may have a shared pathway with HER2, and therefore, contribute to trastuzumab resistance.

 > Subjects and Methods Top

Cell culture and reagents

The human HER2-positive breast cancer cell lines, SKBR3 and HCC1954, and the HER2-negative breast cancer line, MDA-MB-231, were purchased from the Chinese Academy of Medical Sciences Cell Resource Centre/Peking Union Medical College. SKBR3, MDA-MB-231, and HCC1954 cells were cultured in RPMI 1640 (HyClone) at 37°C in humidified atmosphere of 95% air/5% CO2. All mediums were supplemented with 10% fetal bovine serum (Gibco). Trastuzumab was purchased from Genetech. Trastuzumab-resistant SKBR3 cell line (SKBR3/R) was obtained by sustained exposure to 10 μg/mL trastuzumab for 4 months, during which period the medium was renewed after every 4 days and the cells were passaged when they reached 50% confluence. We confirmed trastuzumab resistance by dose-response tests as described below.

Cell viability

Cells were seeded in 96-well microplates at 5 × 104 cells per well. The cell culture medium was replaced with 50 μL 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-serum-free fresh medium and cultured for 4 h. Then, 200 μL dimethylsulfoxide were mixed to dissolve the formazan crystals. Absorbance was measured at 570 nm using Epoch Microplate Spectrophotometer (Bio Tek). The value of IC50 was validated from the dose-dependent growth suppression data.

Transfection of siRNA

H19 lncRNA was knocked down using a specific H19 hairpin siRNA vector (RiboBio, Guangzhou, China). The H19 hairpin siRNA sequence was 5'-CATCAAAGACACCATCGGA-3' that was subcloned into pSilencer 2.1-U6 neovector (shRNAH19). A negative control shRNA not complementary to any known human mRNA was purchased from RiboBio. Cell transfection was conducted, according to the manufacturer's instructions. The transfected cells were selected with 4 μg/mL puromycin. Successful knockdown of erythropoietin receptor (EPOR) expression was verified by western blotting and quantitative real-time polymerase chain reaction (RT-PCR).

RNA isolation and quantitative real-time polymerase chain reaction

Total RNA was extracted from cancer tissues or cells applying the TRIzol reagent (Invitrogen). Concentrations of RNA were analyzed using Epoch spectrophotometry. RNA was reverse transcribed to cDNA using the SuperScript first strand synthesis system (Invitrogen). RT-PCR analyses were performed though Power SYBR Green. The protocols were implemented depending on the manufacturer's instructions. β-actin was amplified as internal control. ABI 7500 RT-PCR system was employed to conduct the quantitative RT-PCR (qRT-PCR) tests. The H19 specific primers were as follows: forward: 5'-ATCGGTGCCTCAGCGTTCGG-3'; reverse: 5'-CTGTCCTCGCCGTCACACCG-3'. The PCR protocol followed was as follows: 5 min at 94°C, followed by 40 cycles of 30 s at 95°C, 30 s at 60°C, and 1 min at 72°C.

Patients and tissue samples

All the patients were ascertained to be HER2-positive by either fluorescence in situ hybridization, immunohistochemistry, or both at our institution from July 2008 to July 2012. The number of patients whose ages are <50 years and ≥50 years is 27 and 21, respectively. The number of patients with H19 high expression whose ages are <50 and ≥50 is 13 and 8, respectively (P = 0.486). All the patients were treated with trastuzumab in the first-line setting. Informed consent was signed by each patient. Staging of tumor was ensured based on the 7th edition of the tumor-node-metastasis (TNM) categorization of the International Union Against Cancer. The cancer tissues were immediately frozen in liquid nitrogen, and then, kept at −80°C.

Statistical analysis

All tests were performed at least three times. All statistics are presented as the mean ± standard deviation and were carried out in the SPSS version 15.0 (SPSS Inc., Chicago, IL, USA). Value of P < 0.05 was considered as statistically significant.

 > Results Top

H19 is a trastuzumab-responsive long non-coding RNAs

The MTT assay was used to assess trastuzumab sensitivity. We investigated the trastuzumab effect on cell viability in our HER2-negative (MDA-MB-231) and HER2-positive (SKBR3 and HCC1954) breast cancer cell lines. We treated the cell lines with trastuzumab for 7 days and observed a reduction of 42% in SKBR3 cell proliferation; however, no changes were observed in MDA-MB-231 or HCC1954 cell lines [Figure 1]a. qRT-PCR manifested a marked increase in the expression of H19 in SKBR3 cells treated with different concentrations of trastuzumab [Figure 1]b. The expression of H19 reminded unaltered in HCC1954 cells [Figure 1]c and MDA-MB-231 cells [Figure 1]d. Therefore, trastuzumab treatment leads to increased expression of H19 in the SKBR3 cell line.
Figure 1: H19 is a trastuzumab-responsive long non-coding RNA. (a) After treatment with trastuzumab for 7 days, we observed a reduction of 42% in SKBR3 cell proliferation by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide method; however, no changes were observed in MDA-MB-231 or HCC1954 cell lines. (b) In the case of quantitative real-time polymerase chain reaction revealed a marked increase in the expression of H19 in SKBR3 cells treated with different concentrations of trastuzumab. (c) The expression of H19 did not alter in HCC1954 cells treated with different concentrations of trastuzumab. (d) The expression of H19 did not alter in MDA-MB-231 cells after treatment with different concentrations of trastuzumab

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Downregulation of H19 sensitizes cells to trastuzumab treatment

Transfection with H19 shRNA resulted in a decrease in viabilities of SKBR3 [Figure 2]a (16% reduction, P = 0.003) and MDA-MB-231 [Figure 2]b (23% reduction, P = 0.04) cells under normal conditions; however, no change was observed in HCC1954 cell line [Figure 2]c. Treatment with 2 μg/mL trastuzumab led to moderate inhibition of cell proliferation in SKBR3 cells compared with scrambled shRNA-transfected cells and parental cells. However, when trastuzumab was added along with H19 shRNA, additive effects on the suppression of cell proliferation were seen compared with either the trastuzumab-treated cells or the cells with H19 downregulation [Figure 2]d. Taken together, these data revealed that effects of H19 downregulation and trastuzumab exposure were synergistic in SKBR3 cell line.
Figure 2: Downregulation of H19 sensitizes cells to trastuzumab treatment. (a) Transfection with H19 shRNA resulted in a decrease in proliferation of SKBR3. (b) Transfection with H19 shRNA resulted in a decrease in proliferation of MDA-MB-231 cells. (c) No change was observed in the HCC1954 cell line when transfected with H19 shRNA. (d) Additive effects on the inhibition of cell proliferation were seen when trastuzumab was added along with H19 shRNA compared with either the trastuzumab-treated cells or cells with H19 downregulation

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The relationship between H19 and the acquired resistance to trastuzumab

We tried to develop trastuzumab-resistant SKBR3 cell lines to mimic the acquired resistance in HER2-positive breast cancer patients. SKBR3 cells, H19 shRNA-transfected SKBR3 cells, and scrambled shRNA-transfected SKBR3 cells were incubated with trastuzumab for 4 months to establish trastuzumab-resistant SKBR3/R, SKBR3-H19-shRNA/R, and SKBR3-scrambled-shRNA/R cells. The cells were then treated with different concentrations of trastuzumab for 120 h, and the viability of the cells after treatment with various trastuzumab concentrations is shown in [Figure 3]a. After treatment with 2 μg/mL trastuzumab, the mean viability for SKBR3-H19-shRNA/R cells was 83% and for SKBR3/R cells was 119%, and both were remarkably higher than that of the parental SKBR3 cells. The IC50 value for trastuzumab was significantly different between parental SKBR3 cells (5.6 μg/mL) and SKBR3/R cells (37.1 μg/mL) [Figure 3]b. SKBR3/R cells became resensitized to trastuzumab after transfection with H19 shRNA but not after transfection with scrambled shRNA [Figure 3]c.
Figure 3: The relationship between H19 and the acquired resistance to trastuzumab. (a) SKBR3, SKBR3/R, SKBR3-H19-shRNA/R, and SKBR3-scrambled-shRNA/R cells were treated with different concentrations of trastuzumab for 120 h, and cell growth inhibition was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. (b) The IC50 value for trastuzumab in resistant cells and the parental cells. The IC50 value for trastuzumab was markedly higher in resistant cells than parental cells. (c) Effects of downregulation of H19 on the sensitivity against 2 μg/mL trastuzumab in SKBR3/R cells. Cell proliferation was assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide method in H19 shRNA-transfected SKBR3/R cells using scrambled shRNA-transfected SKBR3/R and SKBR3/R cells as controls

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H19 expression of human epidermal growth factor receptor 2-positive breast cancer tissues is correlated with patients' pathological characteristics and the patients' response to trastuzumab-based treatment

The H19 expression of tumor tissues in 48 breast cancer patients who underwent trastuzumab-therapy was examined using RT-PCR. We chose 1.178 ng/mL as the cutoff value of H19 to distinguish patients with high H19 expression or low H19 expression, as previously described.[19] [Table 1] summarizes the relationship between clinicopathological characteristics and H19 expression level. The Chi-square or Fisher's exact tests showed that the expression level of H19 was significantly associated with TNM stage (P = 0.049), metastasis (P = 0.049), H19 expression, and Ki67 index (P = 0.033), but not with hormone receptor status, age, or histological grade.
Table 1: The clinical information of the 48 breast cancer patients

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Next, we investigated the relationship between H19 expression in breast cancer tissues of HER2-positive and the clinical response to trastuzumab-contained treatment. Among the 48 HER2-positive breast cancer patients, 21 patients exhibited high H19 expression. Positive clinical response to trastuzumab, which is defined as partial response or complete response of breast cancer patients who have stable disease for ≥6 months, was observed in 9 patients, with progression-free survival (PFS) of 7 months. In the other 27 patients with low H19 expression, 19 patients exhibited positive clinical response and PFS of 11 months. Taken together, these results provided evidence that higher expression of H19 might lead to trastuzumab resistance in HER2-positive breast cancer patients. High H19 expression was associated with a worse clinical prognosis and a lower PFS [Figure 4].
Figure 4: Survival curves were calculated by log-rank method. Patients with high levels of H19 exhibited a significantly poor prognosis than those with low levels of H19 (P = 0.037)

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 > Discussion Top

Treatment of HER2-positive breast cancer has notably improved by the application of anti-HER2 drugs, such as trastuzumab; nevertheless, primary and secondary resistance is a major limitation. There are several potential mechanisms underlying trastuzumab resistance as follows: (1) masking or loss of trastuzumab binding site on HER2. p95HER2 is a truncated isoform generated by HER2 mutation, and p95HER2 exhibits constitutive kinase activity because it lacks the extracellular receptor domain. Therefore, activation of this HER2 mutated isoform leads to resistance to trastuzumab treatment.[20] Besides, mucin-4, which is an O-glycosylated protein, is also a potential binding partner of HER2, and the interaction of mucin-4 and HER2 may cover trastuzumab binding site on HER2.[21] (2) Activation of HER2 downstream signaling pathways reportedly induces trastuzumab resistance. Phosphatase and tensin homolog (PTEN) deficiency or PI3KCA activation was discovered in 20%–25% of HER2-positive breast cancer populations.[22] PTEN deficiency activates the PI3K signaling pathway and leads to resistance to trastuzumab treatment. (3) Another possible trastuzumab resistance mechanism involves failure to stimulate the immune reaction against breast cancer cell; the interleukin6 inflammatory reaction has been demonstrated to amplify the population of cancer stem cells in HER2-positive breast cancer and leads to resistance to trastuzumab.[23] Some of these potential mechanisms have been proved to play a critical role clinically.[24],[25],[26] In our previous studies, we found that EPO and EPOR play a major role in resistance of HER2-positive breast cancer cells to trastuzumab. The secretion and expression of EPOR, p-EPOR, and EPO downstream signaling molecules, p-STAT5 and p-Akt, dramatically enhanced after the development of acquired resistance to trastuzumab in SKBR3 cells. Moreover, this resistance could be partially reversed by EPOR downregulation. Recent progresses in molecular techniques have encouraged the researchers to investigate the lncRNAs as novel biomarkers and their possible roles in the progression of cancer. H19 has been proved to be related to therapeutic resistance in the bladder, liver, lung, and nonsmall-cell lung carcinoma (NSCLC) tumors.[19],[27],[28] Whether lncRNAs contribute to trastuzumab resistance remains largely ambiguous. Thus, we discussed the function of lncRNAs in trastuzumab-resistance of HER2-positive breast cancer.

To our knowledge, this is the first study to show association of H19 with the resistance of HER2-positive breast cancer cells to trastuzumab. To examine the underlying mechanisms of action of lncRNA H19 in trastuzumab resistance of HER2-positive breast cancer, we obtained trastuzumab-resistant SKBR3 cells exposed chronically to trastuzumab in in vitro. We compared trastuzumab resistance with trastuzumab-sensitive breast cancer cell by qRT-PCR and revealed that H19 expression is upregulated in the trastuzumab-resistant cell. Knockdown of H19 could partially restore the sensitivity of SKBR3/R cell. Thus, H19 might act as an oncogene involved in trastuzumab resistance of HER2-positive breast cancer cell. Based on our clinical data, we found that H19 was significantly overexpressed in tumor tissue compared with normal tissue. High expression of H19 is negatively related to patients' response to trastuzumab-treatment. The data in the clinic were consistent with the results of in vitro analyses, which further affirmed our hypothesis.

Notably, previous studies have demonstrated that the upregulated expression of lncRNA H19 is associated with an unfavorable prognosis in many tumors. A meta-analysis demonstrated that high expression of H19 predicted unfavorable prognosis in cervical cancer and uterine corpus endometriosis cancer.[29] Hashad et al. collected samples from 32 gastric cancer patients as text group and 30 healthy volunteers as control group, and demonstrated that upregulated H19 correlated with TNM stages in gastric cancer patients.[30] H19 has previously been demonstrated to play an important role in cisplatin-resistance in lung cancer. Inhibition of H19 expression restored the cisplatin sensitivity in cisplatin-resistant human lung cancer cell line. Downregulation of H19 expression influenced cell migration, cell cycle, and cell apoptosis. Moreover, patients with high H19 expression benefited less from platinum-based chemotherapy than patients with low H19 expression. This indicated that expression of H19 negatively correlated with patients' sensitivity to platinum-based chemotherapy. Recent studies have proved that, in breast cancer cells, H19 is an important downstream target of estrogen receptor-α (ERα), and therefore, altering ERα levels may influence H19 expression that affects the apoptotic response to chemotherapy. The researchers concluded that the ERα-H19-BIK signaling axis plays a critical role in chemoresistance.[31] In this study, we deemed that H19 may play an important oncogenic role related to trastuzumab resistance in HER2-positive breast cancer. H19 sensitization may be a valid intervention in trastuzumab resistance in HER2-positive breast cancer, and thus, H19 might be a potential predictive biomarker of trastuzumab resistance.

Further explorations are imperative to elucidate the mechanisms underlying H19-mediated trastuzumab resistance. It has become increasingly clear that H19 gene is modulated by a complex interaction of both intrinsic and extrinsic factors. The feedback between growth factors and H19 expression might be important to promote breast cancer oncogenesis; HGF induces H19 expression through the phospholipase C and extracellular-signal-regulated kinase (ERK)/mitogen-activated protein kinase pathways, and H19 induces upregulation of tyrosine kinase receptors, containing c-Met and estimated glomerular filtration rate (EGFR), and activated their downstream ERK and AKT signaling pathways. Recently, researchers have found that H19 encoded miR-675, several targets of which have been identified to play crucial roles in many different cancer tissues, including Cadherin 11, CALN1, and Twist 1.[32],[33] Among the known targets of miR-675, Cbl-b, and c-Cbl were the first to demonstrate an interaction with miR-675 though their coding sequences. MicroRNA-675-induced downregulation of Cbl-b and c-Cbl in breast cancer cells was related to a more aggressive phenotype.[18] Low expression of c-Cbl combined with high expression of miR-675 indicates ER-negative phenotype breast cancer tumor, which exhibits poor prognosis. As previously reported, resistance to trastuzumab is commonly associated with tyrosine kinase receptor overexpression, and the tyrosine kinase receptors could act as a connecting link between the microenvironment and tumor cells. Stimulation of c-Cbl activation leads to suppression of proliferation in colon cancer cells and enhancement of EGFR degradation.[34] Similarly, activation of Cbl-b downregulates EGFR expression and induces G1-phase arrest and apoptosis inNSCLC.[35] Therefore, tumor therapeutic drugs can activate Cbl, which, in turn, causes downregulation of tyrosine kinase receptors. However, several growth factors from tumor microenvironment could induce tyrosine kinase receptor activation, which, in turn, could protect the cells from trastuzumab-mediated damage. We hypothesize that downregulation of Cbl through H19-derived miR-675 may play a vital function in resistance of HER2-positive breast cancer cells to trastuzumab.

 > Conclusions Top

We have provided evidence of the oncogenic function of H19 that is associated with trastuzumab resistance. H19 downregulation enhances the therapeutic effect of trastuzumab as well as reverses resistance. H19 might be a reliable marker for predicting the resistance of HER2-positive breast cancer patients to trastuzumab. These findings could provide insight into improved clinical treatment and prediction of HER2-positive breast cancer patient prognosis. Further studies are necessary to demonstrate the underlying mechanisms of the H19-mediated signaling pathway involved in resistance to trastuzumab.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 > References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1]


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