BJC: The "switch" for statins to prevent cancer has been found!

In recent years, the health benefits of statins have continuously refreshed people's awareness
.

For example, Qidian Cake has been introduced in a previous article: Statins may promote a surge of healthy intestinal bacteria in obese patients; it is associated with a 16% reduction in the risk of cancer in patients with heart failure and a 26% reduction in the risk of cancer death
.

Studies have also shown that long-term use of statins is associated with a reduced risk of colorectal cancer, but its mechanism of action is currently unclear
.

Recently, researchers such as James CH Hardwick from Leiden University Medical Center in the Netherlands conducted a large cohort study and found that the use of statins was indeed associated with a 22% reduction in the risk of colorectal cancer
.

In particular, it is worth mentioning that the use of statins is related to the reduced risk of colorectal cancer with positive expression of SMAD4, but has nothing to do with the risk of colorectal cancer with KRAS and BRAF mutations
.

The research results were published in the British journal of cancer, an authoritative journal in the oncology field under the "Nature" publishing house[1]
.

Screenshot of the homepage of the paper.
Statins (lovastatin, simvastatin, rosuvastatin, etc.
) are commonly used clinically lipid-lowering drugs
.

Existing literature evidence shows that the use of statins is related to the risk reduction of colorectal cancer, but this risk reduction varies greatly in different studies [2]
.

Considering that colorectal cancer is a molecularly heterogeneous disease, the sensitivity of statins may vary with molecular subtypes
.

From the point of view of the mechanism of action, statins inhibit the reduction rate of 3-hydroxy-3-methylglutarate coenzyme A (HMG-CoA) in the synthesis of methylglutarate [3]
.

Inhibition of the mevalonic acid pathway will not only destroy the synthesis of cholesterol, but also destroy farnesyl pyrophosphate, which is essential for the preacylation of KRAS
.

Considering that about 40% of colorectal cancers have activated KRAS mutations [4], some researchers speculate that statins reduce the risk of colorectal cancer by inhibiting KRAS, thereby inhibiting the RAS/RAF pathway [5]
.

However, Hardwick proposed a different mechanism of action
.

He believes that statins act on colorectal cancer by activating the bone morphogenetic protein (BMP) pathway [6]
.

This conjecture is based on the evidence that statins activate the BMP pathway in bone [7] and the evidence that the BMP pathway plays a key role in colorectal cancer [8, 9]
.

Specifically, in in vitro and rodent studies, the effects of statins depend on the expression of SMAD4, the core element of the BMP pathway
.

Statins inhibit the growth of SMAD4-positive cancer cells, but promote the growth of SMAD4-negative cancer cells [6]
.

If these findings are true in humans, then the use of statins should reduce the risk of tumors expressing SMAD4
.

In the same way, if statins exert their effects by inhibiting KRAS, the relationship between the use of statins and the reduced risk of colorectal cancer will be affected by KRAS and BRAF activating mutations
.

Therefore, Hardwick’s main purpose is to explore the relationship between the use of statins and the risk of colorectal cancer, and whether this relationship changes with the expression of SMAD4 in the tumor or the presence of KRAS and BRAF mutations
.

To this end, the Hardwick team conducted a large population-based cohort study
.

Information about 69,272 statin users and 94,753 non-statin users were obtained in two registration systems in the Netherlands
.

Overall, compared with the non-statin group, the proportion of men and diabetic patients in the statin group was greater
.

But other than that, there were no significant clinical differences between the two groups in terms of age, follow-up time, inflammatory bowel disease, adenoma resection, use of non-steroidal anti-inflammatory drugs, and postmenopausal hormones
.

During the study period, 1188 people developed colorectal cancer
.

After adjusting for the influence of some factors, they found that the use of statins was associated with a 22% reduction in the risk of colorectal cancer (hazard ratio of 0.
78)
.

With the extension of statin treatment, the risk of colorectal cancer is also reduced
.

The duration of statin treatment and the cumulative incidence of colorectal cancer.
Next, the Hardwick team collected 592 colorectal cancer pathological specimens for molecular subtype analysis, of which 312 were from statin users and 280 were from non-statin users
.

Based on the expression of SMAD4 in tumors, the relationship between the use of statins and the risk of colorectal cancer molecular subtypes was evaluated
.

First Hardwick counted SMAD4 expression and BRAF/KRAS mutations
.

215 cases (37%) had normal SMAD4 expression (SMAD4 positive), and 375 cases (63%) had weak or no SMAD4 expression (SMAD4 negative)
.

The use of statins is associated with a reduced risk of colorectal cancer with normal expression of SMAD4 (odds ratio, 0.
64)
.

At the same time, the use of statins is associated with an increased risk of colorectal cancer with weak or no SMAD4 expression (odds ratio, 1.
54)
.

Let's look at the BRAF and KRAS mutations
.

Among 592 colorectal cancer samples, 88 cases carried BRAF mutations and 144 cases carried KRAS mutations
.

Due to insufficient DNA extraction quality, 59 and 62 samples could not be analyzed for KRAS or BRAF mutations, respectively
.

Based on the mutation status of KRAS and BRAF, Hardwick evaluated the impact of statin use on the molecular subtypes of colorectal cancer, and found that there was no association between statin use and the risk of colorectal cancer with KRAS or BRAF mutations or a combination of both
.

The relationship between statin use and different molecular subtypes of colorectal cancer.
In general, this large cohort study found that compared with non-users, statin users have a significantly lower risk of colorectal cancer and a lower overall risk It is entirely due to the reduced risk of SMAD4-positive colorectal cancer among statin users
.

In addition, the use of statins has nothing to do with the risk of colorectal cancer with KRAS and BRAF mutations
.

It is worth mentioning that this study has several advantages
.

First of all, this is the first population cohort study to explore the relationship between the use of statins and the risk of colorectal cancer from the perspective of molecular pathology and epidemiology
.

Secondly, because the prescription data is obtained directly from the pharmacy, it can avoid the inherent recall bias in the questionnaire method for collecting drug information
.

Third, through the analysis of the users of blockers, the higher incidence of colorectal cancer in cardiovascular disease patients can be controlled.
If this is not done, the effects of statins will be underestimated
.

Of course, this study also has several limitations
.

For example, this study is observational, and it has not adjusted the use of non-steroidal anti-inflammatory drugs and other over-the-counter drugs
.

All in all, the results of this research provide population research evidence for the use of statins in CRC through the SMAD4-dependent mechanism
.

In the future, statins may become a chemical prevention and treatment method for people who have developed SMAD4-positive bowel cancer (such as Lynch syndrome patients)
.

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Chief EditorBioTalkerHommes DW, Ten Dijke P, Offerhaus GJ, Hardwick JC.
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Chief EditorBioTalker