BRCA1, BCL2, and the RB Tumor Suppressor have abnormal expressions in lung cancer

 

Marwa Mohammed Ali Jassim¹, Shaymaa A. Naji², Majid Mohammed Mahmood³

¹College of Dentistry, Al-Muthanna University, Al-Muthanna, Iraq.

²Dep. of Medical Laboratory Techniques, Al- Nisour University College, Baghdad, Iraq.

³Dep. of Biology, College of Science, Mustansiriyah University, Baghdad, Iraq.

 

ABSTRACT:

The retinoblastoma (RB) gene encodes the retinoblastoma pocket protein, which controls the cell cycle by binding to unphosphorylated E2F transcription factors and inhibiting their activation. The function of BRCA1 and the anti-apoptotic protein Bcl-2 in lung cancer, however, is still debated. Objective:The purpose of this research is to look at the relationship between the cell-cycle proteins BRCA1, BCL2, and RB and lung cancer etiology and progression. Experimental Design: Cases from major hospitals and many private histopathological laboratories between 2018 and 2021 were reviewed for immunohistochemical expression of BRCA1, BCL2, and RB. A total of 60 people (20 healthy people as a control group and 40 patients with lung carcinoma) were reviewed and analyzed for immunohistochemical expression of these genes. Results: In (90.0%) of cases, RB-IHC was overexpressed, according to the data. The BRCA1 overexpression was seen in (95.0 %). Though BCL2 was overexpressed in (92.5%) of the cases. When comparing the healthy and lung cancer groups, there is a highly significant difference at (P<0.01). Conclusion: Overexpression of RB, BRCA1, and BCL2 in lung cancers with little or no regulatory role may suggest mutational events, which act in collaboration with numerous other genetic mutations in these tissues. The study findings indicate that disruption of cell cycle proteins may perform a unique function in lung cancer disease onset and development and suggest that all patients have abnormalities in the BRCA1, BCL2, and RB proteins. have a role in lung carcinomas.

 

 

INTRODUCTION:

Lung cancer is a form of cancer that begins in the cells that lining the airways of the lungs. In the globe, it ranks as the second most frequent kind of cancer. In many parts of the world, it is still a major public health issue.The five-year survival rate for people with lung cancer is still around 15% despite advances in staging and the combination of surgery, radiation, and chemotherapy¹. About 80% of all instances of lung cancer are due to non-small cell lung cancer (NSCLC), whereas about 20% of all cases are due to small cell lung cancer (SCLC).

 

 

Non-small cell lung cancers with the most popular cell architecture are adenocarcinoma and squamous cell carcinoma (NSCLC)^2,3.

 

In the United States, tobacco use is the major cause of lung cancer in men and women, with a male-to-female ratio of 90 to 70%⁴. Numerous studies have been undertaken in recent years to investigate the possible involvement of multiple molecular pathways in the formation and progression of lung cancer, including cell cycle and apoptosis regulators, oncogenes and tumor suppressor genes, and cell adhesion molecules^5,6.

 

The BRCA1 genes code for big proteins that are only distantly related to one another in terms of structure. These tumor suppressor genes are widely expressed through the S and G2 stages of cell growth in a variety of tissues and play asignificant role in the DNA double-strand repair process. The BRCA1 is involved in both the cellular and molecular responses to double-strand breaks^7,8. These genes increase the chance of developing a variety of malignancies, including pancreatic and prostate cancer and the progress of hereditary breast and ovarian cancer syndrome^9,10,11. Because the BRCA genes are not known to be responsible for lung cancer mutations, epidemiological studies are required to confirm this.

 

The Bcl-2 gene was initially found in patients with follicular B-cell lymphoma.The Bcl-2 gene is located near the immunoglobulin heavy chain locus' transcriptional enhancer elements due to t (14:18)^12,13. On the other hand, transregulatory mechanisms exist to be involved in the high amounts of Bcl-2 protein production observed in a range of solid tumors, including prostate cancer¹⁴, breast cancer¹⁵, and lung cancer¹⁶. By stopping cells in the G0/G1 phase of the cell cycle, Bcl-2 appears to inhibit programmed cell death (apoptosis)^17,18.

 

Rb (retinoblastoma) gene inactivation is seen in more than 90% of SCLC patients^19,20, making it the most common molecular abnormality in this cancer type.Rb protein phosphorylation is essential for cell proliferation in response to mitogenic stimuli²¹. Cell cycle progression is inhibited by hypophosphorylated retinoma protein complexes on E2F-regulated gene promoters, which form tissue-specific transcriptional repressive complexes. pRb is phosphorylated in response to mitogenic stimuli, which is followed by the activation of cyclin–cyclin-dependent kinases complexes in a sequential manner. This series of events weakens Rb's interaction with members of the E2F1-3 family, allowing cells to go through the cell cycle more quickly. This means that pRb is frequently regarded as the key regulator of the G1-S phase change²².

 

MATERIALS AND METHODS:

This study employed 60 formalin-fixed paraffin-embedded archival tissues, 40 from Iraqi lung cancer patients and 20 from healthy individuals (as control lung tissues group). Each 4-5mm thick piece of the required tissue block was placed on a positively charged slide for use in immunohistochemistry (IHC) assay for evaluating BRCA1, BCL2, and RB expression proteins using monoclonal primary antibodies against them according to the manufacturer's procedure (Abcam/UK). The samples were examined using a light microscope, first at a magnification of 10 and then at a magnification of       40 ²³.

 

AnalyticalStatistics:

Numbers and percentages were used to describe qualitative data, and Pearson Chi2 tests were used to compare interquartile ranges where appropriate. The P values (0.01) and (0.05) were deemed statistically very significant and significant, respectively, based on the statistical significance test.

 

RESULTS AND DISCUSSION:

The immunohistochemical (IHC) expressions for RB proteins are shown in (Table 1). The percentage of lung cancers with low (1+), moderate score (2+) and high (3+) RB-IHC reactions were (17.5%), (32.5%) and (40.0%), respectively. Theseresults showed highly significant differences (P=0.00) in RB scoring. While there are significant differences (P=0.013) according to signal staining.

 

On the other hand, (Table 2) illustrates the total BRCA1-positive percentage in lung carcinomas were (22.5%,30%, and 42.5%, in low, moderate, and strong scores, respectively). In apparently healthy nasal control tissues, the low and moderate signal scores of BRCA1- were observed in (15.0% and 10.0%). There are highly significant differences (P=0.00) between healthy and carcinoma groups regarding the IHC-results for detection of BRCA1.

 

Table 1:The signal scoring and intensityof RB-IHC in healthy and lung carcinomas tissues

RB-IHC Expression		Scoring			Stain		Intensity
		Healthy Control	Lung carcinoma	Pearson Chi-Square (P-value)			Healthy Control	Lung carcinoma	Pearson Chi-Square (P-value)
Negative	N	17	4	P=0.00 Highly  Sign. (P<0.01)	NO stain	N	16	5	P=0.013  Sign. (P<0.05)
	%	85.0%	10.0%			%	80.0%	12.5%
+	N	2	7		Weak	N	4	4
	%	10.0%	17.5%			%	20.0%	10.0%
++	N	1	13		Moderate	N	0	10
	%	5.0%	32.5%			%	0.0%	25.0%
+++	N	0	16		Strong	N	0	21
	%	0.0%	40.0%			%	0.0%	52.5%
Total	N	20	40		Total	N	20	40
	%	100.0%	100.0%			%	100.0%	100.0%
Odds ratio			2.361		Odds ratio			2.421

 

Table 2: Scattering of BRCA1-IHC signal scoring and intensity in cancerous lung tissues

BRCA1-IHC Expression		Scoring			Stain		Intensity
		Healthy Control	Lung carcinoma	Pearson Chi-Square (P-value)			Healthy Control	Lung carcinoma	Pearson Chi-Square (P-value)
Negative	N	15	2	P=0.00 Highly  Sign. (P<0.01)	NO stain	N	18	3	P=0.015  Sign. (P<0.05)
	%	75.0%	5.0%			%	90.0%	7.5%
+	N	3	9		Weak	N	1	6
	%	15.0%	22.5%			%	5.0%	15.0%
++	N	2	12		Moderate	N	1	13
	%	10.0%	30%			%	5.0%	32.5%
+++	N	0	17		Strong	N	0	18
	%	0.0%	42.5%			%	0.0%	45.0%
Total	N	20	40		Total	N	20	40
	%	100.0%	100.0%			%	100.0%	100.0%
Odds ratio			3.441		Odds ratio			2.773

 

Table 3:Expression level of BCL2 scoring and stainingfor healthy and Lung cancer tissues

BCL2-IHC Expression		Scoring			Stain		Intensity
		Healthy Control	Lung carcinoma	Pearson Chi-Square (P-value)			Healthy Control	Lung carcinoma	Pearson Chi-Square (P-value)
Negative	N	19	3	P=0.01 Highly  Sign. (P≤0.01)	NO stain	N	17	5	P=0.027 Sign. (P<0.05)
	%	95.0%	7.5%			%	85.0%	12.5%
+	N	1	5		Weak	N	2	2
	%	5.0%	12.5%			%	10.0%	5.0%
++	N	0	8		Moderate	N	1	11
	%	0.0%	20%			%	5.0%	7.5%2
+++	N	0	24		Strong	N	0	22
	%	0.0%	60.0%			%	0.0%	55.0%
Total	N	20	40		Total	N	20	40
	%	100.0%	100.0%			%	100.0%	100.0%
Odds ratio			1.993		Odds ratio			1.832

 

Furthermore, the results in (table and figure 2) reveal percentages of BCL2-signal scores oflung carcinoma tissues, the low (1+), moderate (2+) signal scores of were (12.5%) and (20%), respectively. Whereas high signal scores (3+) constituted  (60.0%). There are highly considerable  differences (P=0.01 ) according to BCL2-IHC expression.

 

Lung cancer has been connected to the inactivation of the retinoblastoma (Rb) gene, which has been demonstrated in a variety of different types of cancer. Immunohistochemistry analysis of lung cancer revealed that 7 (88 percent) of small cell lung carcinomas lacked RB protein expression, indicating that mutations in this gene may contribute to tumor progress^24,25. An further research¹⁹ by Dosaka Akita et al.²⁶ revealed that  (21%) of the 91 non-small cell lung cancers tested had negative Rb protein expression.

 

On the other hand, in 19 (16%) of the cases evaluated by (Xu et al., 1996)²⁷, there was absence of RB nuclear staining, which indicated loss of RB function.Expression of Rb was detected immunohistochemically in 80% of the 208 non-small cell lung cancers (NSCLCs)in an investigation done by (Nishio et al., 1997)²⁸.

 

Dosaka‐Akita, et al.,2000²⁹ demonstrated that all 27 small cell lung cancer (SCLC) samples tested failed to demonstrate positive nuclear immunostaining for the RB protein (RB-) in the nucleus. The presence of Rb gene mutations in SCLC raises the possibility that this gene is implicated in the etiology of this frequent adult malignancy.

 

When combined with the existence of additional cancer-causing mutations in genes, such as RB loss, it is possible to induce carcinogenesis in a variety of different types of tissue. This shows that RB may be implicated in the beginning and/or development of cancers that were previously unknown to be associated with it^30,31. It is worth noting that RB inactivation is discovered in about 90% of sporadicsmall cell lung cancers (SCLC), suggesting that it may have had a role in their development³². These findings also suggest that RB may perform a variety of activities depending on the kind of cancer tissue and the time of development of the tumor³³.

 

(Leonettiet al., 2021)³⁴ showed the complete absence of Rb at IHC and RB baseline alterations in histological examination of small cell lung cancer.

 

In addition to regulating the cellular response to chemotherapy, the BRCA1 tumor suppressor protein also plays a role in many other critical physiological functions.Because of the distinction between breast and ovarian cancer, BRCA1 does not have a role in the development of NSCLC^35,36.

In addition to hereditary breast and ovarian cancers, the BRCA1 gene has been linked to a variety of other cancer forms. However, as noted by the author, further investigation into their relationship to lung cancer is needed (Lee et al., 2020)³⁷.

 

Lung cancer is not more likely to progress in those with the BRCA1 mutation. It is demonstrated by these studies that BRCA1 is a transcription factor that regulates cell cycle progression and that BRCA1 is a predictor of clinical prostate cancer prognosis³⁸.

 

More than 2.97% of people are affected by a BRCA1 mutation. The most common types of cancer when BRCA1 mutations are detected include lung and breast cancers as well as colon and high grade ovarian serous cancers as well as urinary bladder urothelial carcinomas., BRCA1 mutations (2.34%), nonsense mutations (0.32%), fusion mutations (0.12%), amplification mutations (0.11%), and loss mutations (0.11%) are the most prevalent BRCA1 changes (0.05 percent ). Furthermore, Lewis et al., 2014³⁹ and AACR, 2017⁴⁰ report that BRCA1 is mutated in 1.99% of small cell lung carcinoma patients and 3.45 percent of lung carcinoma patients.

 

Bcl-2 has been studied extensively as a prognostic marker for lung cancer, particularly small cell carcinoma. However, the results have been contradictory and debated in the scientific community. (Zhang et al., 2015)⁴¹ released an updated meta-analysis that included 50 studies evaluating Bcl-2's predictive value.This meta-analysis from 2015 includes 6,863 lung cancer patients in its scope. Non-small cell lung cancerNSCLC tumors have been shown to exhibit Bcl-2 in 33% of the cases.It appears that in both Asian and non-Asian research groups, NSCLC patients with Bcl-2 positive tumors had a better prognosis than those with Bcl-2 negative tumors. It's worth noting that Bcl-2 may have a dual function in the development of cancer. Experiments have shown that greater Bcl-2 expression leads to a poorer prognosis rather than a longer survival period.This work also shows that the precise role of Bcl-2 in regulating apoptosis may be affected by the cell environment⁴².

 

There were 50 patients with advanced lung cancer who had their tumors pathologically validated, and 18 healthy controls who were examined. The anti-Bcl-2 monoclonal coated antibody was used to measure the amounts of Bcl-2 in the blood serum.Compared to the control group, serum Bcl-2 levels were significantly higher in 48(96 percent) of advanced lung cancer patients (p<0.001), and the serum Bcl-2 level was considered diagnostic in lung cancer patients⁴³.

 

Due to the findings of the current study, reduced apoptosis occurred in lung cancer patients, which may have been caused by the influence of elevated blood Bcl-2 levels. More research, however, is needed to fully understand the involvement of Bcl-2 in lung cancer. High levels of RB, BRCA1, and BCL2 protein expression in malignant lung tissues may indicate the presence of mutational events in these proteins, which may have only a limited or no regulatory role in normal lung tissues and organs.

 

ACKNOWLEDGMENTS:

The authors would like to state that this research was not funded by any institution and that the research was done without any financial support, and was self-expenditure on their part.

 

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Accepted on 31.01.2022           © RJPT All right reserved

Research J. Pharm. and Tech 2022; 15(9):4083-4087.